Difference between revisions of "Ewing sarcoma"
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− | + | <span id="BackToTop"></span> | |
− | + | <div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px"> | |
− | + | [[#top|Back to Top]] | |
− | + | </div> | |
− | |<big>[[ | + | {{#lst:Editorial board transclusions|sarcoma}} |
− | + | <big>'''Note: certain regimens have been moved to dedicated pages: | |
− | + | *'''[[Ewing sarcoma, pediatric|Pediatric Ewing sarcoma]] | |
+ | </big> | ||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
|- | |- | ||
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{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
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=Guidelines= | =Guidelines= | ||
− | ==[ | + | '''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.''' |
− | *[ | + | ==[https://www.esmo.org/ ESMO]== |
− | + | *'''2009:''' [https://doi.org/10.1093/annonc/mdp155 Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454436/ PubMed] | |
− | *[https://www.nccn.org/ | + | **'''2008:''' Paulussen et al. [https://doi.org/10.1093/annonc/mdn103 Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456785/ PubMed] |
+ | **'''2007:''' Saeter. [https://doi.org/10.1093/annonc/mdm048 Ewing's sarcoma of bone: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491059/ PubMed] | ||
+ | **'''2005:''' Saeter et al. [https://doi.org/10.1093/annonc/mdi811 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Ewing's sarcoma of bone] [https://pubmed.ncbi.nlm.nih.gov/15888765/ PubMed] | ||
+ | **'''2003:''' Saeter. [https://doi.org/10.1093/annonc/mdg335 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Ewing's sarcoma of bone] [https://pubmed.ncbi.nlm.nih.gov/12881370/ PubMed] | ||
+ | ==NCCN== | ||
+ | *''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418 NCCN Guidelines - Bone Cancer].'' | ||
=Neoadjuvant therapy= | =Neoadjuvant therapy= | ||
− | |||
==EVAIA {{#subobject:4d4fee|Regimen=1}}== | ==EVAIA {{#subobject:4d4fee|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin | EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:11e269|Variant=1}}=== | ===Regimen {{#subobject:11e269|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)] |
− | |style="background-color:#1a9851"|Phase | + | |1992-1997 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-esc) |
− | |style="background-color:#ffffbf"| | + | |[[#VAIA|VAIA]] |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36 | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen is intended for high-risk patients.'' | + | ''Note: This regimen is intended for high-risk patients.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
Line 48: | Line 52: | ||
**Note: primary reference does not comment about the use of mesna | **Note: primary reference does not comment about the use of mesna | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | ||
− | + | '''21-day cycle for 4 cycles''' | |
− | '''21-day cycle for 4 cycles | + | </div> |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | ==== | + | ====Subsequent treatment==== |
− | *Surgical removal of tumors is done when possible. | + | *[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible. |
− | * | + | *EICESS-92, patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: Definitive [[external beam radiotherapy]] x 5440 cGy, then adjuvant [[#EVAIA_2|EVAIA]] |
− | * | + | *EICESS-92, patients with a good histologic response: Adjuvant [[External beam radiotherapy]] 4480 cGy, then adjuvant [[#EVAIA_2|EVAIA]] |
*Additional details about particular clinical scenarios can be found in the original reference | *Additional details about particular clinical scenarios can be found in the original reference | ||
− | + | </div></div> | |
− | |||
− | |||
===References=== | ===References=== | ||
− | # Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [ | + | # '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150/ PubMed] [https://clinicaltrials.gov/study/NCT00002516 NCT00002516] |
− | |||
==VACA {{#subobject:4a10e9|Regimen=1}}== | ==VACA {{#subobject:4a10e9|Regimen=1}}== | ||
− | |||
− | |||
− | |||
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VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin | VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin | ||
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ===Regimen variant #1 {{#subobject:72ab30|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/NEJMoa020890 Grier et al. 2003 (INT-0091)] |
− | |style="background-color:#1a9851"|Phase | + | |1988-1992 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
|[[#VACA.2FIE|VACA/IE]] | |[[#VACA.2FIE|VACA/IE]] | ||
|style="background-color:#d73027"|Inferior OS | |style="background-color:#d73027"|Inferior OS | ||
Line 82: | Line 82: | ||
|} | |} | ||
''Note: The survival disadvantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.'' | ''Note: The survival disadvantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
Line 87: | Line 88: | ||
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> | **Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> | ||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
− | *[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative | + | *[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup> |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule |
− | *[[Mesna (Mesnex)]] after | ||
− | |||
'''21-day cycle for 17 cycles''' | '''21-day cycle for 17 cycles''' | ||
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | ==== | + | ====Subsequent treatment==== |
− | *Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins. | + | *Definitive local therapy is planned to take place on week 12 |
− | ** | + | *[[Surgery#Surgical_resection|Surgery]] can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins. |
+ | **INT-0091, residual tumor after surgery: 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin | ||
*If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy | *If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:c30ab5|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)] |
+ | |1986-01 to 1991-07 | ||
|style="background-color:#91cf61"|Non-randomized | |style="background-color:#91cf61"|Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen is intended for standard risk patients.'' | + | ''Note: This regimen is intended for standard risk patients.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
Line 115: | Line 119: | ||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43 | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] "as appropriate" | *[[Mesna (Mesnex)]] "as appropriate" | ||
− | |||
'''9-week "block", then proceed to local therapy:''' | '''9-week "block", then proceed to local therapy:''' | ||
− | |||
====Local therapy==== | ====Local therapy==== | ||
− | *Complete surgical removal of tumors is done when possible. | + | *Complete [[Surgery#Surgical_resection|surgical removal]] of tumors is done when possible. |
− | * | + | *CESS 86, patients not undergoing surgery: [[External beam radiotherapy]] 6000 cGy to the tumor bulk, with the tumor-bearing compartment receiving at least 4480 cGy |
− | * | + | *CESS 86, patients with incomplete surgical resection or poor histologic response: [[External beam radiotherapy]] 4480 cGy |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#VACA_2| | + | *Adjuvant [[#VACA_2|VACA]] |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [ | + | # '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014/ PubMed] |
− | # Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. [ | + | # '''INT-0091:''' Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS; CCG; POG. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. [https://doi.org/10.1056/NEJMoa020890 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12594313/ PubMed] |
− | |||
==VACA/IE {{#subobject:ed89d8|Regimen=1}}== | ==VACA/IE {{#subobject:ed89d8|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
VACA/IE: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | VACA/IE: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | ||
− | == | + | <div class="toccolours" style="background-color:#c8a2c8"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/NEJMoa020890 Grier et al. 2003 (INT-0091)] |
− | |style="background-color:#1a9851"|Phase | + | |1988-1992 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[#VACA|VACA]] | |[[#VACA|VACA]] | ||
− | |style="background-color:#1a9850"|Superior OS | + | |style="background-color:#1a9850"|Superior OS<sup>1</sup> |
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>The survival advantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis. The dosing schedule below assumes that the patient is doxorubicin-naive.'' |
− | ====Chemotherapy, VACA portion==== | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Induction {{#subobject:2f582d|Variant=1}}=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VACA portion (cycles 1 & 3)==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1 | *[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1 | ||
− | |||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Supportive therapy, VACA portion (cycles 1 & 3)==== | |
− | + | *[[Mesna (Mesnex)]] after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule | |
− | ====Supportive | + | ====Chemotherapy, IE portion (cycles 2 & 4)==== |
− | *[[Mesna (Mesnex)]] after | + | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, with mesa |
− | |||
− | |||
− | |||
− | ====Chemotherapy, IE portion==== | ||
− | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Supportive therapy, IE portion (cycles 2 & 4)==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] with ifosfamide; primary reference did not list dosage/schedule |
− | *[[Mesna (Mesnex)]] with | + | '''21-day cycle for 4 cycles, followed by:''' |
− | + | </div></div><br> | |
− | '''21-day cycle | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Definitive=== | |
''Local therapy is planned to take place on week 12, as follows:'' | ''Local therapy is planned to take place on week 12, as follows:'' | ||
− | == | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins. | + | *[[Surgery#Surgical_resection|Surgery]] can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins. |
− | ** | + | **INT-0091, residual tumor after surgery: 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin |
*If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy | *If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy | ||
− | + | </div></div><br> | |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Consolidation=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VACA portion==== | ||
+ | *[[Vincristine (Oncovin)]] as follows: | ||
+ | **Cycles 5, 7, 9, 11, 13: 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
+ | *[[Doxorubicin (Adriamycin)]] as follows: | ||
+ | **Cycle 5: 75 mg/m<sup>2</sup> IV bolus once on day 1 | ||
+ | **Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> | ||
+ | *[[Cyclophosphamide (Cytoxan)]] as follows: | ||
+ | **Cycles 5, 7, 9, 11, 13: 1200 mg/m<sup>2</sup> IV once on day 1 | ||
+ | *[[Dactinomycin (Cosmegen)]] as follows: | ||
+ | **Cycles 7, 9, 11, 13: 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup> | ||
+ | ====Supportive therapy, VACA portion (cycles 5, 7, 9, 11, 13)==== | ||
+ | *[[Mesna (Mesnex)]] after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule | ||
+ | ====Chemotherapy, IE portion (cycles 6, 8, 10, 12)==== | ||
+ | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, with mesna | ||
+ | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
+ | ====Supportive therapy, IE portion (cycles 6, 8, 10, 12)==== | ||
+ | *[[Mesna (Mesnex)]] with ifosfamide; primary reference did not list dosage/schedule | ||
+ | '''21-day cycle for 13 cycles (17 total cycles of chemotherapy)''' | ||
+ | </div></div></div> | ||
===References=== | ===References=== | ||
− | # Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. [ | + | # '''INT-0091:''' Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. [https://doi.org/10.1056/NEJMoa020890 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12594313/ PubMed] |
==VAIA {{#subobject:84f65e|Regimen=1}}== | ==VAIA {{#subobject:84f65e|Regimen=1}}== | ||
− | + | VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>A</u>'''ctinomycin-D (Dactinomycin) | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1 {{#subobject:195911|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, | + | !style="width: 20%"|Study |
− | === | + | !style="width: 20%"|Dates of enrollment |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)] |
− | |style="background-color:#1a9851"|Phase | + | |1992-1997 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
|[[#EVAIA|EVAIA (high-risk)]] | |[[#EVAIA|EVAIA (high-risk)]] | ||
− | |style="background-color:#ffffbf"| | + | |style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36 |
|- | |- | ||
|} | |} | ||
''Note: high-risk patients were randomized to this regimen versus EVAIA. Standard-risk patients were not randomized at this point of the protocol.'' | ''Note: high-risk patients were randomized to this regimen versus EVAIA. Standard-risk patients were not randomized at this point of the protocol.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1 | ||
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4 | *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4 | ||
− | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3 | + | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
+ | **Note: primary reference does not comment about the use of mesna | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | ||
− | |||
'''21-day cycle for 4 cycles, then proceed to local therapy:''' | '''21-day cycle for 4 cycles, then proceed to local therapy:''' | ||
− | |||
====Local therapy==== | ====Local therapy==== | ||
− | *Surgical removal of tumors is done when possible. | + | *[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible. |
− | * | + | *EICESS-92, patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: [[External beam radiotherapy]] 5440 cGy |
− | * | + | *EICESS-92, patients with a good histologic response: [[External beam radiotherapy]] 4480 cGy |
*Additional details about particular clinical scenarios can be found in the original reference | *Additional details about particular clinical scenarios can be found in the original reference | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *EICESS-92, high-risk patients: Adjuvant [[#VAIA_2|VAIA]] |
− | * | + | *EICESS-92, standard-risk patients: Adjuvant [[#VAIA_2|VAIA]] versus [[#VACA_2|VACA]] |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:fc21ca|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)] |
+ | |1986-01 to 1991-07 | ||
|style="background-color:#91cf61"|Non-randomized | |style="background-color:#91cf61"|Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen is intended for high risk patients.'' | + | ''Note: This regimen is intended for high risk patients.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
Line 234: | Line 258: | ||
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44 | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44 | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] "as appropriate" | *[[Mesna (Mesnex)]] "as appropriate" | ||
− | |||
'''9-week "block", then proceed to local therapy:''' | '''9-week "block", then proceed to local therapy:''' | ||
− | |||
====Local therapy==== | ====Local therapy==== | ||
− | *Complete surgical removal of tumors is done when possible. | + | *Complete [[Surgery#Surgical_resection|surgical removal]] of tumors is done when possible. |
− | * | + | *CESS 86, patients not undergoing surgery: [[External beam radiotherapy]] 6000 cGy to the tumor bulk, with the tumor-bearing compartment receiving at least 4480 cGy |
− | * | + | *CESS 86, patients with incomplete surgical resection or poor histologic response: [[External beam radiotherapy]] 4480 cGy |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *Adjuvant [[#VAIA_2|VAIA]] | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014/ PubMed] | ||
+ | # '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150/ PubMed] [https://clinicaltrials.gov/study/NCT00002516 NCT00002516] | ||
+ | #'''CWS/RMS-96:''' Sparber-Sauer M, Ferrari A, Kosztyla D, Ladenstein R, Cecchetto G, Kazanowska B, Scarzello G, Ljungman G, Milano GM, Niggli F, Alaggio R, Vokuhl C, Casanova M, Klingebiel T, Zin A, Koscielniak E, Bisogno G. Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer. 2022 Sep;69(9):e29691. Epub 2022 Apr 19. [https://doi.org/10.1002/pbc.29691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35441463/ PubMed] | ||
+ | ==VDC/IE {{#subobject:5bcde5|Regimen=1}}== | ||
+ | VDC/IE: '''<u>V</u>'''incristine, '''<u>D</u>'''oxorubicin, '''<u>C</u>'''yclophosphamide, alternating with '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide | ||
+ | <br>VAdriaC/IE: '''<u>V</u>'''incristine, '''<u>Adria</u>'''mycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, alternating with '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, q2wk {{#subobject:47963f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ Womer et al. 2012 (COG AEWS0031)] | ||
+ | |2001-05 to 2005-08 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[#VDC.2FIE|VDC/IE]]; standard | ||
+ | | style="background-color:#91cf60" |Seems to have superior EFS (primary endpoint) | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082251/ DuBois et al. 2023 (COG AEWS1221)] | ||
+ | |2014-12 to 2019-03 | ||
+ | | style="background-color:#1a9851" |Phase 3 (C) | ||
+ | |[[#VDC.2FIE_.26_Ganitumab_999|VDC/IE & Ganitumab]] | ||
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of EFS | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VDC portion (cycles 1, 3, 5)==== | ||
+ | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
+ | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy, VDC portion (cycles 1, 3, 5)==== | ||
+ | *[[Mesna (Mesnex)]] with cyclophosphamide (dose/schedule not specified) | ||
+ | *[[Filgrastim (Neupogen)]] schedule not specified | ||
+ | ====Chemotherapy, IE portion (cycles 2, 4, 6)==== | ||
+ | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, with mesna | ||
+ | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
+ | ====Supportive therapy, IE portion (cycles 2, 4, 6)==== | ||
+ | *[[Mesna (Mesnex)]] with ifosfamide; primary reference did not list dosage/schedule | ||
+ | *[[Filgrastim (Neupogen)]] schedule not specified | ||
+ | '''14-day cycle for 6 cycles (VDC/IE x 3)''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *Definitive local therapy, then adjuvant [[#VDC.2FIE_888|VDC/IE]] | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, q2wk with extra vincristine {{#subobject:4ug63f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677904/ Leavey et al. 2021 (COG AEWS1031)] | ||
+ | |2010-11-22 to 2016-01-04 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#VDC.2FIE.2FVTC_999|VDC/IE/VTC]] | ||
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of EFS | ||
+ | |- | ||
+ | |} | ||
+ | ''Note: the only difference between this and the variant above is the additional dose of vincristine in the second week of each VDC cycle.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VDC portion (cycles 1, 3, 5)==== | ||
+ | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | ||
+ | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Chemotherapy, IE portion (cycles 2, 4, 6)==== | ||
+ | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
+ | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
+ | ====Supportive therapy, both portions (cycles 1 to 6)==== | ||
+ | *[[Filgrastim (Neupogen)]] details not specified | ||
+ | '''14-day cycle for 6 cycles (VDC/IE x 3)''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[# | + | *Definitive local therapy, then [[#VDC.2FIE_888|VDC/IE]] continuation |
− | + | </div></div><br> | |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, q3wk {{#subobject:6c6df0|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ Womer et al. 2012 (COG AEWS0031)] | ||
+ | |2001-05 to 2005-08 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#VDC.2FIE|VDC/IE]]; dose-intense | ||
+ | | style="background-color:#fc8d59" |Seems to have inferior EFS | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VDC portion (cycles 1 & 3)==== | ||
+ | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
+ | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy, VDC portion (cycles 1 & 3)==== | ||
+ | *[[Mesna (Mesnex)]] with cyclophosphamide; primary reference did not list dosage/schedule | ||
+ | *[[Filgrastim (Neupogen)]] | ||
+ | ====Chemotherapy, IE portion (cycles 2 & 4)==== | ||
+ | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, with mesna | ||
+ | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
+ | ====Supportive therapy, IE portion (cycles 2 & 4)==== | ||
+ | *[[Mesna (Mesnex)]] with ifosfamide; primary reference did not list dosage/schedule | ||
+ | *[[Filgrastim (Neupogen)]] | ||
+ | '''21-day cycle for 4 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *Definitive local therapy, then adjuvant [[#VDC.2FIE_888|VDC/IE]] | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # '''COG AEWS0031:''' Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR; Children's Oncology Group. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012 Nov 20;30(33):4148-54. Epub 2012 Oct 22. Erratum in: J Clin Oncol. 2015 Mar 1;33(7):814. Dosage error in article text. [https://doi.org/10.1200/jco.2011.41.5703 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23091096/ PubMed] [https://clinicaltrials.gov/study/NCT00006734 NCT00006734] |
− | # | + | ##'''Update:''' Cash T, Krailo MD, Buxton AB, Pawel BR, Healey JH, Binitie O, Marcus KJ, Grier HE, Grohar PJ, Reed DR, Weiss AR, Gorlick R, Janeway KA, DuBois SG, Womer RB. Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031. J Clin Oncol. 2023 Oct 20;41(30):4724-4728. Epub 2023 Aug 31. [https://doi.org/10.1200/jco.23.00053 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37651654/ PubMed] |
+ | # '''COG AEWS1031:''' Leavey PJ, Laack NN, Krailo MD, Buxton A, Randall RL, DuBois SG, Reed DR, Grier HE, Hawkins DS, Pawel B, Nadel H, Womer RB, Letson GD, Bernstein M, Brown K, Maciej A, Chuba P, Ahmed AA, Indelicato DJ, Wang D, Marina N, Gorlick R, Janeway KA, Mascarenhas L. Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report. J Clin Oncol. 2021 Dec 20;39(36):4029-4038. Epub 2021 Oct 15. [https://doi.org/10.1200/jco.21.00358 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677904/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34652968/ PubMed] [https://clinicaltrials.gov/study/NCT01231906 NCT01231906] | ||
+ | #'''COG AEWS1221:''' DuBois SG, Krailo MD, Glade-Bender J, Buxton A, Laack N, Randall RL, Chen HX, Seibel NL, Boron M, Terezakis S, Hill-Kayser C, Hayes A, Reid JM, Teot L, Rakheja D, Womer R, Arndt C, Lessnick SL, Crompton BD, Kolb EA, Daldrup-Link H, Eutsler E, Reed DR, Janeway KA, Gorlick RG. Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2023 Apr 10;41(11):2098-2107. Epub 2023 Jan 20. [https://doi.org/10.1200/JCO.22.01815 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082251/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36669140/ PubMed] [https://clinicaltrials.gov/study/NCT02306161 NCT02306161] | ||
==VIDE {{#subobject:be5278|Regimen=1}}== | ==VIDE {{#subobject:be5278|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:6b3582|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1002/pbc.20820 Juergens et al. 2006 (EURO-E.W.I.N.G. 99)] |
− | + | |NR | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1200/jco.21.01942 Koch et al. 2022 (Ewing 2008R3)] |
− | |style="background-color:#91cf61"| | + | |2009-2018 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV push once on day 1 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV push once on day 1 | ||
Line 271: | Line 418: | ||
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 1000 mg/m<sup>2</sup> IV push once on day 1; 60 minutes prior to ifosfamide, then 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours (total dose per cycle: 10,000 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 1000 mg/m<sup>2</sup> IV push 1 | ||
*2 to 3 liters/m<sup>2</sup> hydration per day | *2 to 3 liters/m<sup>2</sup> hydration per day | ||
− | *Recommended, but not required: [[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day | + | *Recommended, but not required: [[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 4 to 13, starting 24 hours after completion of chemotherapy |
− | + | '''21-day cycle for 6 cycles''' | |
− | '''21-day cycle for 6 | + | </div> |
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *Further therapy is dictated by patient characteristics & response; details can be found in the primary reference | + | *EURO-E.W.I.N.G. 99: Further therapy is dictated by patient characteristics & response; details can be found in the primary reference |
− | + | *Ewing 2008R3: Surgery when feasible followed by adjuvant [[#VAC_888|VAC]] x 8 or [[#VAI|VAI]] x 8, then [[#Treosulfan_.26_Melphalan.2C_then_auto_HSCT_999|Treosulfan & Melphalan, then auto HSCT]] consolidation versus [[#Observation_888|No further treatment]] | |
− | === | + | </div></div><br> |
− | {| class="wikitable" style="width: | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #2 {{#subobject:bd4d04|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003] |
− | |style="background-color:#91cf61"|Phase | + | |1998-01 to 1999-06 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
Line 295: | Line 447: | ||
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous | + | '''21-day cycle for up to 6 cycles''' |
− | + | </div> | |
− | '''21-day cycle for up to 6 | + | <div class="toccolours" style="background-color:#cbd5e7"> |
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *Strauss et al. 2003, patients with resectable localized disease: complete [[Surgery#Surgical_resection|surgical removal]] of tumors when possible, then adjuvant [[#VAI|VAI]] |
− | * | + | *Strauss et al. 2003, patients with unresectable localized disease: [[#VAI|VAI & RT]] consolidation |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [ | + | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818/ PubMed] |
− | # '''EURO-E.W.I.N.G. 99:''' Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-EWING 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. [https:// | + | # '''EURO-E.W.I.N.G. 99:''' Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-EWING 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. [https://doi.org/10.1002/pbc.20820 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16572419/ PubMed] |
− | # '''Euro-EWING99-R1:''' Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. [ | + | # '''Euro-EWING99-R1:''' Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. [https://doi.org/10.1200/JCO.2013.54.4833 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/24982464/ PubMed] [https://clinicaltrials.gov/study/NCT00020566 NCT00020566] |
+ | #'''Ewing 2008R3:''' Koch R, Gelderblom H, Haveman L, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Eich HT, Renard M, Hauser P, Burdach S, Bovee J, Bonar F, Reichardt P, Kruseova J, Hardes J, Kühne T, Kessler T, Collaud S, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Hong A, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Metzler M, Hartmann W, Hjorth L, Bhadri V, Dirksen U. High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. J Clin Oncol. 2022 Jul 20;40(21):2307-2320. Epub 2022 Apr 15. [https://doi.org/10.1200/jco.21.01942 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/35427190/ PubMed] [https://clinicaltrials.gov/study/NCT00987636 NCT00987636] | ||
+ | #'''EURO EWING 2012:''' Brennan B, Kirton L, Marec-Bérard P, Gaspar N, Laurence V, Martín-Broto J, Sastre A, Gelderblom H, Owens C, Fenwick N, Strauss S, Moroz V, Whelan J, Wheatley K. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet. 2022 Oct 29;400(10362):1513-1521. [https://doi.org/10.1016/s0140-6736(22)01790-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36522207/ PubMed] | ||
+ | #'''Ewing 2008R1:''' Koch R, Haveman L, Ladenstein R, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Kager L, Renard M, Hauser P, Burdach S, Bovee JVMG, Hong AM, Reichardt P, Kruseova J, Streitbürger A, Kühne T, Kessler T, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Bonar F, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Hartmann W, Hjorth L, Bhadri VA, Metzler M, Gelderblom H, Dirksen U. Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial. Clin Cancer Res. 2023 Dec 15;29(24):5057-5068. [https://doi.org/10.1158/1078-0432.ccr-23-1966 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37843857/ PubMed] EudraCT 2008-003658-13 | ||
=Adjuvant therapy= | =Adjuvant therapy= | ||
+ | ==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}== | ||
+ | BuMel: '''<u>Bu</u>'''sulfan & '''<u>Mel</u>'''phalan | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:75d2e0|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997] | ||
+ | |NR | ||
+ | | style="background-color:#ffffbe" |Phase 2, fewer than 20 pts | ||
+ | | style="background-color:#d3d3d3" | | ||
+ | | style="background-color:#d3d3d3" | | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090/ Whelan et al. 2018 (R2Loc)] | ||
+ | |2000-2015 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-esc) | ||
+ | |[[Ewing_sarcoma#VAI|VAI]] | ||
+ | | style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *Neoadjuvant [[#VIDE|VIDE]] x 6, then [[Surgery#Surgical_resection|surgery]], then adjuvant [[#VAI|VAI]] x 1 | ||
+ | </div> | ||
+ | {{#lst:Autologous HSCT|75d2e0}} | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. [https://doi.org/10.1038/sj.bmt.1700992 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9404924/ PubMed] | ||
+ | # '''R2Loc:''' Whelan J, Le Deley MC, Dirksen U, Le Teuff G, Brennan B, Gaspar N, Hawkins DS, Amler S, Bauer S, Bielack S, Blay JY, Burdach S, Castex MP, Dilloo D, Eggert A, Gelderblom H, Gentet JC, Hartmann W, Hassenpflug WA, Hjorth L, Jimenez M, Klingebiel T, Kontny U, Kruseova J, Ladenstein R, Laurence V, Lervat C, Marec-Berard P, Marreaud S, Michon J, Morland B, Paulussen M, Ranft A, Reichardt P, van den Berg H, Wheatley K, Judson I, Lewis I, Craft A, Juergens H, Oberlin O; Euro-EWING-99 and EWING-2008 Investigators. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-EWING99 and Ewing-2008. J Clin Oncol. 2018 Nov 1;36(31):3110-9. Epub 2018 Sep 6. [https://doi.org/10.1200/JCO.2018.78.2516 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30188789/ PubMed] [https://clinicaltrials.gov/study/NCT00020566 NCT00020566] | ||
==EVAIA {{#subobject:a56448|Regimen=1}}== | ==EVAIA {{#subobject:a56448|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin | EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:342685|Variant=1}}=== | ===Regimen {{#subobject:342685|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1992-1997 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen is intended for high-risk patients.'' | + | ''Note: This regimen is intended for high-risk patients.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#EVAIA| | + | *Neoadjuvant [[#EVAIA|EVAIA]], then [[Surgery#Surgical_resection|local therapy]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
Line 336: | Line 526: | ||
**Note: primary reference does not comment about the use of Mesna (Mesnex) | **Note: primary reference does not comment about the use of Mesna (Mesnex) | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | ||
− | |||
'''21-day cycle for 10 cycles''' | '''21-day cycle for 10 cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [ | + | # '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150/ PubMed] [https://clinicaltrials.gov/study/NCT00002516 NCT00002516] |
==VACA {{#subobject:f92366|Regimen=1}}== | ==VACA {{#subobject:f92366|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin | VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin | ||
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ===Regimen variant #1 {{#subobject:835ca4|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)] |
− | |style="background-color:#1a9851"|Phase | + | |1992-1997 |
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
|[[#VAIA_2|VAIA]] | |[[#VAIA_2|VAIA]] | ||
− | |style="background-color:#ffffbf"| | + | |style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36 |
|- | |- | ||
|} | |} | ||
''Note: this regimen was intended for standard-risk patients.'' | ''Note: this regimen was intended for standard-risk patients.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VAIA| | + | *Neoadjuvant [[#VAIA|VAIA]], then [[Surgery#Surgical_resection|local therapy]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1 | ||
Line 369: | Line 560: | ||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | ||
− | |||
'''21-day cycle for 10 cycles''' | '''21-day cycle for 10 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:26bab6|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)] |
+ | |1986-01 to 1991-07 | ||
|style="background-color:#91cf61"|Non-randomized | |style="background-color:#91cf61"|Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen is intended for standard risk patients.'' | + | ''Note: This regimen is intended for standard risk patients.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VACA| | + | *Neoadjuvant [[#VACA|VACA]], then [[Surgery#Surgical_resection|local therapy]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
Line 389: | Line 585: | ||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43 | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] "as appropriate" | *[[Mesna (Mesnex)]] "as appropriate" | ||
− | |||
'''9-week "block" for 3 blocks''' | '''9-week "block" for 3 blocks''' | ||
− | + | </div></div><br> | |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3 {{#subobject:26bab6|Variant=1}}=== | ||
+ | {| class="wikitable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/s0959-8049(97)00043-9 Craft et al. 1997 (ET-1)] | ||
+ | |1978-1986 | ||
+ | |style="background-color:#91cf61"|Non-randomized (RT) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *Induction [[#CAV_888|VAC]], then [[#Cyclophosphamide.2C_Vincristine.2C_RT|Cyclophosphamide, Vincristine, RT]] with consideration for surgery | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1 | ||
+ | *[[Doxorubicin (Adriamycin)]] as follows: | ||
+ | **Cycles 1, 3, 5, 7: 50 mg/m<sup>2</sup> IV once on day 1 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> (maximum dose of 1000 mg) IV once on day 1 | ||
+ | *[[Dactinomycin (Cosmegen)]] as follows: | ||
+ | **Cycles 2, 4, 6, 8, 12, 14, 16, 18: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
+ | '''21-day cycle for 18 cycles (1 year)''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [ | + | # '''ET-1:''' Craft AW, Cotterill SJ, Bullimore JA, Pearson D; United Kingdom Children's Cancer Study Group; Medical Research Council Bone Sarcoma Working Party. Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). Eur J Cancer. 1997 Jun;33(7):1061-9. [https://doi.org/10.1016/s0959-8049(97)00043-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9376188/ PubMed] |
− | # Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [ | + | # '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014/ PubMed] |
+ | # '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150/ PubMed] [https://clinicaltrials.gov/study/NCT00002516 NCT00002516] | ||
==VAI {{#subobject:560a3d|Regimen=1}}== | ==VAI {{#subobject:560a3d|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide | VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide | ||
− | === | + | <br>IVA: '''<u>I</u>'''fosfamide, '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !Study | + | ===Regimen variant #1, capped dactinomycin {{#subobject:9b2e40|Variant=1}}=== |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !Comparator | + | !style="width: 20%"|Study |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Dates of enrollment |
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/JCO.2013.54.4833 Le Deley et al. 2014 (Euro-EWING99-R1)] |
− | | style="background-color:#1a9851" |Phase | + | |2000-2010 |
− | |VAC | + | | style="background-color:#1a9851" |Phase 3 (C) |
− | | style="background-color:#ffffbf" |Inconclusive whether non-inferior | + | |[[#VAC_999|VAC]] |
+ | | style="background-color:#ffffbf" |Inconclusive whether non-inferior EFS | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VIDE| | + | *Neoadjuvant [[#VIDE|VIDE]] x 6, then complete [[Surgery#Surgical_resection|surgical excision]] if feasible; radiotherapy if surgery incomplete or infeasible |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
− | *[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> (maximum dose of 1.5 mg | + | *[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> (maximum dose of 1.5 mg) IV once per day on days 1 & 2 |
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2 | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] is not described | *[[Mesna (Mesnex)]] is not described | ||
− | |||
'''21-day cycle for 8 cycles''' | '''21-day cycle for 8 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2, uncapped dactinomycin {{#subobject:ddb896|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003] |
− | |style="background-color:#91cf61"|Phase | + | |1998-01 to 1999-06 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VIDE| | + | *Neoadjuvant [[#VIDE|VIDE]], then [[Surgery#Surgical_resection|local therapy]] if it was possible |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
Line 446: | Line 675: | ||
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2 | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
*If appropriate, concurrent radiation therapy given sometime during the first 3 cycles | *If appropriate, concurrent radiation therapy given sometime during the first 3 cycles | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous | ||
− | |||
'''21-day cycle for up to 8 cycles''' | '''21-day cycle for up to 8 cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for | + | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818/ PubMed] |
− | # '''Euro-EWING99-R1:''' Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. [ | + | # '''Euro-EWING99-R1:''' Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. [https://doi.org/10.1200/JCO.2013.54.4833 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24982464/ PubMed] [https://clinicaltrials.gov/study/NCT00020566 NCT00020566] |
− | |||
==VAIA {{#subobject:05e476|Regimen=1}}== | ==VAIA {{#subobject:05e476|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>A</u>'''ctinomycin-D (Dactinomycin) |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:f72b80|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)] |
− | + | |1992-1997 | |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:#1a9851"|Phase | ||
|[[#VACA_2|VACA (standard-risk)]] | |[[#VACA_2|VACA (standard-risk)]] | ||
− | |style="background-color:#ffffbf"| | + | |style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36 |
|- | |- | ||
|} | |} | ||
''Note: standard-risk patients were randomized to this regimen versus VACA. High-risk patients were not randomized at this point of the protocol.'' | ''Note: standard-risk patients were randomized to this regimen versus VACA. High-risk patients were not randomized at this point of the protocol.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VAIA| | + | *Neoadjuvant [[#VAIA|VAIA]], then [[Surgery#Surgical_resection|local therapy]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1 | ||
Line 484: | Line 712: | ||
**Note: primary reference does not comment about the use of mesna | **Note: primary reference does not comment about the use of mesna | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 | ||
− | |||
'''21-day cycle for 10 cycles''' | '''21-day cycle for 10 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:7bd984|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)] |
+ | |1986-01 to 1991-07 | ||
|style="background-color:#91cf61"|Non-randomized | |style="background-color:#91cf61"|Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen | + | ''Note: This regimen was intended for high risk patients.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VAIA| | + | *Neoadjuvant [[#VAIA|VAIA]], then [[Surgery#Surgical_resection|local therapy]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
Line 504: | Line 737: | ||
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44 | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44 | ||
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | *[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] "as appropriate" | *[[Mesna (Mesnex)]] "as appropriate" | ||
− | |||
'''9-week "block" for 3 blocks''' | '''9-week "block" for 3 blocks''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [ | + | # '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014/ PubMed] |
− | # Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [ | + | # '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150/ PubMed] [https://clinicaltrials.gov/study/NCT00002516 NCT00002516] |
− | |||
=Relapsed or refractory or metastatic= | =Relapsed or refractory or metastatic= | ||
− | |||
==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}== | ==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1, PO busulfan, mel 140 mg/m<sup>2</sup> {{#subobject:75d2e0|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997] | ||
+ | |NR | ||
+ | | style="background-color:#ffffbe" |Phase 2, fewer than 20 pts | ||
|- | |- | ||
− | |||
|} | |} | ||
− | === | + | {{#lst:Autologous HSCT|75d2e0}} |
− | {| class="wikitable" style="width: | + | </div></div><br> |
− | !style="width: | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #2, PO busulfan, mel 160 mg/m<sup>2</sup> {{#subobject:75d2e1|Variant=1}}=== |
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997] |
− | | style="background-color:#ffffbe" |Phase | + | |NR |
+ | | style="background-color:#ffffbe" |Phase 2, fewer than 20 pts | ||
|- | |- | ||
|} | |} | ||
− | {{#lst:Autologous HSCT| | + | {{#lst:Autologous HSCT|75d2e1}} |
− | === | + | </div></div><br> |
− | {| class="wikitable" style="width: | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #3, IV busulfan {{#subobject:a61951|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003] |
− | | style="background-color:#91cf61" |Phase | + | |1998-01 to 1999-06 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
''Note that melphalan is reported as given on day 2 (not day -2) in the original reference but this is surely an error.'' | ''Note that melphalan is reported as given on day 2 (not day -2) in the original reference but this is surely an error.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VAI_2|VAI]] x 1 or more cycles | + | *Adjuvant [[#VAI_2|VAI]] x 1 or more cycles |
+ | </div> | ||
{{#lst:Autologous HSCT|a61951}} | {{#lst:Autologous HSCT|a61951}} | ||
+ | </div> | ||
+ | |||
===References=== | ===References=== | ||
− | # Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. [https:// | + | # Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. [https://doi.org/10.1038/sj.bmt.1700992 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9404924/ PubMed] |
− | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [ | + | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818/ PubMed] |
− | |||
==Cyclophosphamide & Topotecan {{#subobject:2535b6|Regimen=1}}== | ==Cyclophosphamide & Topotecan {{#subobject:2535b6|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1, standard-dose {{#subobject:f13281|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | === | + | !style="width: 33%"|Dates of enrollment |
− | {| class="wikitable" style="width: | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2001.19.15.3463 Saylors et al. 2001] |
− | |style="background-color:#91cf61"|Phase | + | |NR |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, given first | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first''' |
− | *[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, given second | + | *[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given second''' |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy |
− | *500 mL/m/2 fluids PO | + | *[[:Category:Emesis_prevention|Antiemetics]] once per day on days 1 to 5, prior to chemotherapy |
− | *Antiemetics | + | *3 liters/m<sup>2</sup> IV or PO over 24 hours after chemotherapy |
− | *3 liters/m<sup>2</sup> PO | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 1500/μL above nadir |
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting on day 6, to continue until ANC is at least 1500/ | ||
− | |||
'''21-day cycle for 12 to 14 cycles''' | '''21-day cycle for 12 to 14 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2, standard-dose with local therapy {{#subobject:c531e2|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/pbc.20719 Hunold et al. 2006] |
− | |style="background-color:#91cf61"|Phase | + | |1998-09 to 2004-04 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that | + | ''Note: Some guidelines state that vincristine can be added to this regimen. No primary reference for this is available.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | ||
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | *[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]], antiemetics, fluids, and [[Filgrastim (Neupogen)]] "according to institutional standards" | *[[Mesna (Mesnex)]], antiemetics, fluids, and [[Filgrastim (Neupogen)]] "according to institutional standards" | ||
− | |||
'''21-day cycle for 12 to 14 cycles''' | '''21-day cycle for 12 to 14 cycles''' | ||
− | + | </div> | |
− | ==== | + | <div class="toccolours" style="background-color:#cbd5e7"> |
− | *Surgical removal of tumors is done when possible. | + | ====Subsequent treatment==== |
− | *[[External beam radiotherapy]] | + | *Hunold et al. 2006, surgical candidate lesions: [[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible. |
− | + | *Hunold et al. 2006, all other lesions: Definitive [[External beam radiotherapy]] | |
− | === | + | </div></div><br> |
− | {| class="wikitable" style="width: | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #3, high-dose {{#subobject:230266|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/1096-911X%2820001101%2935:5%3C468::AID-MPO5%3E3.0.CO;2-P Kushner et al. 2000] |
+ | |NR | ||
|style="background-color:#91cf61"|Non-randomized | |style="background-color:#91cf61"|Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup>/day IV continuous | + | *[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given second''' (total dose per cycle: 4200 mg/m<sup>2</sup>) |
− | **Children 10 years or younger received 70 mg/kg/day IV continuous | + | **Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 140 mg/kg) |
− | *[[Topotecan (Hycamtin)]] 2 mg/m<sup>2</sup>/day IV continuous | + | *[[Topotecan (Hycamtin)]] 2 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given third''' (total dose per cycle: 6 mg/m<sup>2</sup>) |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 2100 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given first''' (total dose per cycle: 6300 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 2100 mg/m<sup>2</sup>/day IV continuous | + | **Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 210 mg/kg) |
− | **Children 10 years or younger received 70 mg/kg/day IV continuous | ||
***If body surface area less than 1 m<sup>2</sup>, mesna is given in 500 mL NS over 24 hours | ***If body surface area less than 1 m<sup>2</sup>, mesna is given in 500 mL NS over 24 hours | ||
***If body surface area is at least 1 m<sup>2</sup>, mesna is given in 1000 mL NS over 24 hours | ***If body surface area is at least 1 m<sup>2</sup>, mesna is given in 1000 mL NS over 24 hours | ||
− | *On day 1, prior to chemotherapy, 20 mL/kg | + | *On day 1, prior to chemotherapy, 20 mL/kg NS IV over 30 minutes, then D5 1/2 NS with 15 mEq KCl per 500 mL at 200 mL/m<sup>2</sup>/H until urine specific gravity less than 1.010, then start mesna & cyclophosphamide |
*Additional hydration fluid on days 1 & 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3000 mL/m<sup>2</sup>/24 hours | *Additional hydration fluid on days 1 & 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3000 mL/m<sup>2</sup>/24 hours | ||
*Additional hydration fluid on day 3 at 150 mL/m<sup>2</sup>/hour for 6 to 12 hours after completion of cyclophosphamide infusion | *Additional hydration fluid on day 3 at 150 mL/m<sup>2</sup>/hour for 6 to 12 hours after completion of cyclophosphamide infusion | ||
*Cyclophosphamide is given in D5NS with 10 mEq potassium chloride (KCl) and 5 mg [[Furosemide (Lasix)]] per 500 mL fluid. 500 mL total volume is used for patients with body surface area less than 1 m<sup>2</sup>; 1000 mL total volume is used for patients with BSA of at least 1 m<sup>2</sup> | *Cyclophosphamide is given in D5NS with 10 mEq potassium chloride (KCl) and 5 mg [[Furosemide (Lasix)]] per 500 mL fluid. 500 mL total volume is used for patients with body surface area less than 1 m<sup>2</sup>; 1000 mL total volume is used for patients with BSA of at least 1 m<sup>2</sup> | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 5, to continue until ANC is at least 1000/μL |
− | + | '''Subsequent cycles to start when ANC greater than 1000/μL and platelets greater than 75 x 10<sup>9</sup>/L''' | |
− | '''Subsequent cycles to start when ANC greater than 1000/ | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | # Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000 Nov;35(5):468-74. [https:// | + | # Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000 Nov;35(5):468-74. [https://doi.org/10.1002/1096-911X%2820001101%2935:5%3C468::AID-MPO5%3E3.0.CO;2-P link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11070479/ PubMed] |
− | # Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. [ | + | # Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. [https://doi.org/10.1200/jco.2001.19.15.3463 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11481351/ PubMed] |
− | # Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006 Nov;47(6):795-800. [https:// | + | # Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006 Nov;47(6):795-800. [https://doi.org/10.1002/pbc.20719 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16411206/ PubMed] |
− | |||
==Docetaxel & Gemcitabine {{#subobject:f4062c|Regimen=1}}== | ==Docetaxel & Gemcitabine {{#subobject:f4062c|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:a99189|Variant=1}}=== | ===Regimen {{#subobject:a99189|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable" style="width: 40%; text-align:center;" |
− | !style="width: | + | !style="width: 25%"|Study |
− | !style="width: | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] |
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/cncr.23586 Navid et al. 2008] |
|style="background-color:#ffffbe"|Retrospective | |style="background-color:#ffffbe"|Retrospective | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. Only 2 of the 22 patients in this retrospective review had Ewing sarcoma.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Docetaxel (Taxotere)]] 75 to 100 mg/m<sup>2</sup> IV over 60 minutes on day 8, '''given second''' | + | *[[Docetaxel (Taxotere)]] 75 to 100 mg/m<sup>2</sup> IV over 60 minutes once on day 8, '''given second''' |
− | *[[Gemcitabine (Gemzar)]] 675 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8 | + | *[[Gemcitabine (Gemzar)]] 675 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8, '''given first on day 8''' |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Ondansetron (Zofran)]] once per day on days 1 & 8, prior to chemotherapy |
− | *[[Ondansetron (Zofran)]] | + | *[[Dexamethasone (Decadron)]] starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel |
− | *[[Dexamethasone (Decadron)]] starting either the day before or the day of | ||
*H1 or H2 blockers such as [[Diphenhydramine (Benadryl)]] and [[Ranitidine (Zantac)]] prior to chemotherapy on days 1 & 8 per physician discretion | *H1 or H2 blockers such as [[Diphenhydramine (Benadryl)]] and [[Ranitidine (Zantac)]] prior to chemotherapy on days 1 & 8 per physician discretion | ||
*Some patients received [[Filgrastim (Neupogen)]] starting on day 9 | *Some patients received [[Filgrastim (Neupogen)]] starting on day 9 | ||
− | |||
'''21-day cycles''' | '''21-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''Retrospective:''' Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. [https:// | + | # '''Retrospective:''' Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. [https://doi.org/10.1002/cncr.23586 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18484657/ PubMed] |
− | |||
==ICE {{#subobject:456f0a|Regimen=1}}== | ==ICE {{#subobject:456f0a|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
ICE: '''<u>I</u>'''fosfamide, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide | ICE: '''<u>I</u>'''fosfamide, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:d99fb7|Variant=1}}=== | ===Regimen {{#subobject:d99fb7|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005 (CCG-0894)] |
− | |style="background-color:#91cf61"|Phase | + | |1992-06 to 1994-11 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005 (CCG-0924)] | ||
+ | |1993-07 to 1995-04 | ||
+ | |style="background-color:#91cf61"|Phase 1, >20 pts | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005 (CCG-0931)] | ||
+ | |1994-05 to 1996-12 | ||
+ | | style="background-color:#ffffbe" |Non-randomized, <20 pts | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. The reference did not mention [[Mesna (Mesnex)]] being used.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
Line 682: | Line 937: | ||
**Note: the reference did not explicitly say which 2 days carboplatin should be given on | **Note: the reference did not explicitly say which 2 days carboplatin should be given on | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*Depending on the study the patients were enrolled on, they received one of the following: | *Depending on the study the patients were enrolled on, they received one of the following: | ||
− | **CCG-0894: [[Filgrastim (Neupogen)]] 5 or 10 mcg/kg | + | **CCG-0894: [[Filgrastim (Neupogen)]] 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/μL, or until ANC is at least 1000/μL above nadir, whichever comes later |
− | **CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m<sup>2</sup> once per day or 500 mcg/m<sup>2</sup> | + | **CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m<sup>2</sup> SC once per day or 500 mcg/m<sup>2</sup> SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/μL or platelet count is at least 900 x 10<sup>9</sup>/L for 2 days between days 13 to 18, or until ANC is at least 1000/μL and platelet count is at least 100 x 10<sup>9</sup>/L, whichever comes later |
− | **CCG-0931: [[Filgrastim (Neupogen)]] 5 mcg/kg | + | **CCG-0931: [[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/μL, and IL-6 is continued until platelets are at least 100 x 10<sup>9</sup>/L for 2 consecutive days or until day 35, whichever comes sooner. |
− | + | '''21-day cycles''', with next cycle starting as soon as ANC is at least 1000/μL and platelet count is at least 100 x 10<sup>9</sup>/L | |
− | '''21-day cycles''', with next cycle starting as soon as ANC is at least 1000/ | + | </div> |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | |||
+ | ====Subsequent treatment==== | ||
+ | *Resection of disease was allowed after 4 cycles based on patient's response to ICE | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. [https:// | + | # Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. [https://doi.org/10.1002/pbc.20227 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15503297/ PubMed] |
− | |||
==IE {{#subobject:ba75ef|Regimen=1}}== | ==IE {{#subobject:ba75ef|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
IE: '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | IE: '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:4cd5c8|Variant=1}}=== | ===Regimen {{#subobject:4cd5c8|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1987.5.8.1191 Miser et al. 1987] |
− | |style="background-color:#91cf61"|Phase | + | |1985-06 to 1986-06 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second, | + | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second, with loading dose of mesna''' |
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first''' | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first''' | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 360 mg/m<sup>2</sup> IV loading dose over 1 hour, '''given with ifosfamide''', then 120 mg/m<sup>2</sup>/hour IV over 3 hours, then 360 mg/m<sup>2</sup> IV or PO over 15 minutes every 3 hours for 6 doses, '''given at hours 5, 8, 11, 14, 17, 20''' |
− | *[[Mesna (Mesnex)]] | ||
− | |||
− | |||
− | |||
− | |||
'''21-day cycle for 12 cycles''' | '''21-day cycle for 12 cycles''' | ||
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
+ | *Miser et al. 1987, patients responding to therapy after 4 cycles: local therapy with [[Surgery#Surgical_resection|surgery]] or radiation is used to try to achieve a complete remission. | ||
+ | **Radiation therapy consisted of 180 cGy fractions given for a total dose of 50 to 5500 cGy. | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, Wesley R, Magrath I. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987 Aug;5(8):1191-8. [ | + | # Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, Wesley R, Magrath I. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987 Aug;5(8):1191-8. [https://doi.org/10.1200/jco.1987.5.8.1191 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3114435/ PubMed] |
− | |||
==Irinotecan & Temozolomide {{#subobject:2e2a5c|Regimen=1}}== | ==Irinotecan & Temozolomide {{#subobject:2e2a5c|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1 {{#subobject:c62d11|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | === | + | !style="width: 33%"|Dates of enrollment |
− | {| class="wikitable" style="width: | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1158/1078-0432.ccr-03-0175 Wagner et al. 2004] |
− | |style="background-color:#ffffbe"|Phase | + | |2002-01 to 2003-02 |
+ | |style="background-color:#ffffbe"|Phase 1, fewer than 20 pts | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. Note that irinotecan 15 mg/m<sup>2</sup> was also studied, but this dose was not recommended due to dose-limiting toxicities of diarrhea and infection.'' | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. Note that irinotecan 15 mg/m<sup>2</sup> was also studied, but this dose was not recommended due to dose-limiting toxicities of diarrhea and infection.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Irinotecan (Camptosar)]] 10 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 8 to 12, '''given after temozolomide''' | + | *[[Irinotecan (Camptosar)]] 10 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 8 to 12, '''given second on days 1 to 5, 1 hour after temozolomide''' |
− | *[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5, ''' | + | *[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5, '''given first''' |
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Loperamide (Imodium)]] prn diarrhea | *[[Loperamide (Imodium)]] prn diarrhea | ||
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:620185|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable" style="width: 40%; text-align:center;" |
− | !style="width: | + | !style="width: 25%"|Study |
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/pbc.22206 Casey et al. 2009] |
|style="background-color:#ffffbe"|Retrospective | |style="background-color:#ffffbe"|Retrospective | ||
|- | |- | ||
|} | |} | ||
− | ''Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' | + | ''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Irinotecan (Camptosar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 8 to 12, '''given after temozolomide''' | + | *[[Irinotecan (Camptosar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 8 to 12, '''given second on days 1 to 5, 1 hour after temozolomide''' |
− | *[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5, ''' | + | *[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5, '''given first''' |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Cefixime (Suprax)]] prophylaxis starting 1 to 2 days prior to irinotecan, continuing until the completion of each cycle |
− | *[[Cefixime (Suprax)]] prophylaxis starting 1 to 2 days prior to | + | *Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg PO three times per day during irinotecan therapy |
− | *Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg PO | ||
*[[Loperamide (Imodium)]] prn diarrhea | *[[Loperamide (Imodium)]] prn diarrhea | ||
*Patient "advised to maintain hydration" | *Patient "advised to maintain hydration" | ||
− | |||
'''21-day cycles''' | '''21-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''Phase I:''' Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004 Feb 1;10(3):840-8. [ | + | # '''Phase I:''' Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004 Feb 1;10(3):840-8. [https://doi.org/10.1158/1078-0432.ccr-03-0175 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14871959/ PubMed] |
− | # '''Retrospective:''' Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007 Feb;48(2):132-9. [https:// | + | # '''Retrospective:''' Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007 Feb;48(2):132-9. [https://doi.org/10.1002/pbc.20697 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16317751/ PubMed] |
− | # '''Retrospective:''' Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, Meyers PA. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009 Dec;53(6):1029-34. [https:// | + | # '''Retrospective:''' Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, Meyers PA. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009 Dec;53(6):1029-34. [https://doi.org/10.1002/pbc.22206 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19637327/ PubMed] |
− | |||
==TC, then IE, VDoxoC, VEC {{#subobject:c31c79|Regimen=1}}== | ==TC, then IE, VDoxoC, VEC {{#subobject:c31c79|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
TC, then IE, VDoxoC, VEC: '''<u>T</u>'''opotecan, '''<u>C</u>'''yclophosphamide followed by '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide, then '''<u>V</u>'''incristine, '''<u>Doxo</u>'''rubicin, '''<u>C</u>'''yclophosphamide, then '''<u>V</u>'''incristine, '''<u>E</u>'''toposide, '''<u>C</u>'''yclophosphamide | TC, then IE, VDoxoC, VEC: '''<u>T</u>'''opotecan, '''<u>C</u>'''yclophosphamide followed by '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide, then '''<u>V</u>'''incristine, '''<u>Doxo</u>'''rubicin, '''<u>C</u>'''yclophosphamide, then '''<u>V</u>'''incristine, '''<u>E</u>'''toposide, '''<u>C</u>'''yclophosphamide | ||
− | == | + | <div class="toccolours" style="background-color:#c8a2c8"> |
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.02.1717 Bernstein et al. 2006 (POG 9457)] |
− | |style="background-color:#91cf61"|Phase | + | |NR |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ''This | + | ''Note: This was a complex regimen, and it is suggested to refer to the primary reference and figure 1 for the protocol schema. One arm of patients in this trial received [[Amifostine (Ethyol)]], but its usage is not described below since it did not result in improved outcomes. Treatment starts with an optional topotecan window for stable patients without significantly impaired function or life-threatening disease:'' |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Topotecan window {{#subobject:87b074|Variant=1}}=== | |
− | *[[Topotecan (Hycamtin)]] 2.4 mg/m<sup>2</sup> | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | + | ====Chemotherapy==== | |
− | ====Supportive | + | *[[Topotecan (Hycamtin)]] 2.4 mg/m<sup>2</sup> IV once per day on days 1 to 5 |
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting on day 6, to continue until ANC is at least 5000/ | + | ====Supportive therapy==== |
− | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/μL above nadir | |
'''5-day course, followed by upfront window, starting at week 0:''' | '''5-day course, followed by upfront window, starting at week 0:''' | ||
− | + | </div></div><br> | |
− | ====Upfront window==== | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Upfront window=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy==== | ||
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | *[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | ||
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first''' | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first''' | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*Prehydration with 500 mL/m<sup>2</sup> D5 1/4 NS | *Prehydration with 500 mL/m<sup>2</sup> D5 1/4 NS | ||
− | *1500 mL/m<sup>2</sup> PO | + | *1500 mL/m<sup>2</sup> IV or PO hydration continuous for 24 hours after chemotherapy |
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting on day 6, to continue until ANC is at least 5000/ | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/μL above nadir |
− | |||
'''21-day cycle for up to 2 cycles''' | '''21-day cycle for up to 2 cycles''' | ||
− | |||
''Patients with progression after the first cycle moved immediately to induction therapy; others proceeded to induction after the second cycle, starting at week 6 with IE:'' | ''Patients with progression after the first cycle moved immediately to induction therapy; others proceeded to induction after the second cycle, starting at week 6 with IE:'' | ||
− | + | </div></div><br> | |
− | ====Induction | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Induction=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, IE portion==== | ||
*[[Ifosfamide (Ifex)]] as follows: | *[[Ifosfamide (Ifex)]] as follows: | ||
− | ** | + | **Cycle 1: 3600 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, after etoposide''' |
***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS | ***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS | ||
− | ** | + | **Cycles 2 & 3: 2800 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, after etoposide''' |
***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS | ***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 minutes once per day on days 1 to 5, '''given first, before ifosfamide''' | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 minutes once per day on days 1 to 5, '''given first, before ifosfamide''' | ||
**Administered in 250 mL/m<sup>2</sup> of D5 1/2 NS | **Administered in 250 mL/m<sup>2</sup> of D5 1/2 NS | ||
− | + | ====Supportive therapy, IE portion==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] 4000 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Mesna (Mesnex)]] 4000 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
*"Vigorous hydration" | *"Vigorous hydration" | ||
*Antiemetics | *Antiemetics | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | |||
'''21-day cycle for a total of 3 cycles, alternating with VDoxoC''' | '''21-day cycle for a total of 3 cycles, alternating with VDoxoC''' | ||
− | + | ====Chemotherapy, VDoxoC portion==== | |
− | ==== | + | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV bolus once per day on days 1, 8, 15, '''given first''' |
− | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV bolus once per day on days 1, 8, 15, '''given first | + | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given third''' (total dose per cycle: 75 mg/m<sup>2</sup>) |
− | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous | ||
**Administered in 2400 mL/m<sup>2</sup>/day (4800 mL/m<sup>2</sup> total volume) of D5 1/2 NS | **Administered in 2400 mL/m<sup>2</sup>/day (4800 mL/m<sup>2</sup> total volume) of D5 1/2 NS | ||
− | *[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup> | + | *[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, '''given second''' |
**Administered in 200 mL/m<sup>2</sup> D5 1/2 NS | **Administered in 200 mL/m<sup>2</sup> D5 1/2 NS | ||
− | + | ====Supportive therapy, VDoxoC portion==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] 2400 mg/m<sup>2</sup> total dose IV; exact schedule not specified by reference | *[[Mesna (Mesnex)]] 2400 mg/m<sup>2</sup> total dose IV; exact schedule not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting on day 4, 24 hours after chemotherapy is complete | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 4, 24 hours after chemotherapy is complete |
− | |||
'''21-day cycle for a total of 2 cycles, alternating with IE''' | '''21-day cycle for a total of 2 cycles, alternating with IE''' | ||
− | |||
''Local therapy for primary disease along with ongoing chemotherapy starts at week 21:'' | ''Local therapy for primary disease along with ongoing chemotherapy starts at week 21:'' | ||
− | + | </div></div><br> | |
− | ==== | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Definitive therapy, primary=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VDoxoC portion==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | ||
− | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous | + | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>) |
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Supportive therapy, VDoxoC portion==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]], dosage & schedule not specified by reference | *[[Mesna (Mesnex)]], dosage & schedule not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | + | '''21-day course, followed by local control:''' | |
− | '''21-day | + | ====Local therapy, after week 21==== |
− | |||
− | ====Local | ||
*Choice of modality between surgical and radiation therapy options is at the discretion of the provider | *Choice of modality between surgical and radiation therapy options is at the discretion of the provider | ||
− | * | + | *POG 9457, patients treated with radiation alone: [[External beam radiotherapy]] 4500 cGy in 180 cGy fractions to the initial tumor volume; additional treatment up to a total of 5580 cGy was administered to original bony tumors and the postinduction chemotherapy soft tissue volumes plus a 2 cm margin |
*See primary reference for details about radiation therapy in a variety of clinical scenarios | *See primary reference for details about radiation therapy in a variety of clinical scenarios | ||
− | + | ====Chemotherapy, VEC portion==== | |
− | ==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Supportive therapy, VEC portion==== | |
− | ====Supportive | ||
*Use of [[Mesna (Mesnex)]] not specified by reference | *Use of [[Mesna (Mesnex)]] not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | |||
'''21-day cycle for 2 cycles, followed by:''' | '''21-day cycle for 2 cycles, followed by:''' | ||
− | + | </div></div><br> | |
− | ====Continuation | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | *[[Ifosfamide (Ifex)]] 2100 mg/m<sup>2</sup> | + | ===Continuation=== |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, IE portion==== | ||
+ | *[[Ifosfamide (Ifex)]] 2100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Supportive therapy, IE portion==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]], dosage & schedule not specified by reference | *[[Mesna (Mesnex)]], dosage & schedule not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | |||
'''21-day cycle for a total of 2 cycles, alternating with VDoxoC''' | '''21-day cycle for a total of 2 cycles, alternating with VDoxoC''' | ||
− | + | ====Chemotherapy, VDoxoC portion==== | |
− | ==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15 | ||
− | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous | + | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>) |
− | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> | + | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 |
− | + | ====Supportive therapy, VDoxoC portion==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] dosage & schedule not specified by reference | *[[Mesna (Mesnex)]] dosage & schedule not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | + | '''21-day course, in between IE''' | |
− | '''21-day | ||
− | |||
''Local therapy for metastatic disease along with ongoing chemotherapy starts at week 39:'' | ''Local therapy for metastatic disease along with ongoing chemotherapy starts at week 39:'' | ||
− | + | </div></div><br> | |
− | ==== | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Definitive therapy, metastases=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy, VDoxoC potion==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | ||
**Note: the day 8 dose is not described in the text but is described in figure 1 | **Note: the day 8 dose is not described in the text but is described in figure 1 | ||
− | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous | + | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>) |
− | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> | + | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 |
− | + | ====Supportive therapy, VDoxoC portion==== | |
− | ====Supportive | ||
*[[Mesna (Mesnex)]] dosage & schedule not specified by reference | *[[Mesna (Mesnex)]] dosage & schedule not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | + | '''21-day course, followed by local control of metastatic disease:''' | |
− | '''21-day | + | ====Local therapy, metastatic disease (after week 39)==== |
− | |||
− | ====Local | ||
*Choice of modality between surgical and radiation therapy options is at the discretion of the provider | *Choice of modality between surgical and radiation therapy options is at the discretion of the provider | ||
*[[External beam radiotherapy]] could be used to treat up to three sites of metastatic disease | *[[External beam radiotherapy]] could be used to treat up to three sites of metastatic disease | ||
*See primary reference for details about radiation therapy in a variety of clinical scenarios | *See primary reference for details about radiation therapy in a variety of clinical scenarios | ||
− | + | ====Chemotherapy, VEC portion==== | |
− | ==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8 | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Supportive therapy, VEC portion==== | |
− | ====Supportive | ||
*Use of [[Mesna (Mesnex)]] not specified by reference | *Use of [[Mesna (Mesnex)]] not specified by reference | ||
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting 24 to 48 hours after completion of chemotherapy | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy |
− | |||
'''21-day cycle for 2 cycles''' | '''21-day cycle for 2 cycles''' | ||
− | + | </div></div></div> | |
===References=== | ===References=== | ||
− | # Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group | + | # '''POG 9457:''' Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group; Children's Oncology Group. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006 Jan 1;24(1):152-9. [https://doi.org/10.1200/jco.2005.02.1717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16382125/ PubMed] [https://clinicaltrials.gov/study/NCT00002643 NCT00002643] |
==VAdCA {{#subobject:dd0198|Regimen=1}}== | ==VAdCA {{#subobject:dd0198|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
VAdCA: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin | VAdCA: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:cb5fae|Variant=1}}=== | ===Regimen {{#subobject:cb5fae|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2004.01.041 Miser et al. 2004] |
− | |style="background-color:#1a9851"|Phase | + | |1988-1992 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
|[[#VAdCA.2FIE|VAdCA/IE]] | |[[#VAdCA.2FIE|VAdCA/IE]] | ||
− | |style="background-color:#ffffbf"| | + | |style="background-color:#ffffbf"|Did not meet co-primary endpoints of EFS/OS |
|- | |- | ||
|} | |} | ||
''Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.'' | ''Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1 | ||
Line 958: | Line 1,192: | ||
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses) | **Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses) | ||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
− | *[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative | + | *[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup> |
− | |||
'''21-day cycle for 17 cycles''' | '''21-day cycle for 17 cycles''' | ||
− | + | ====Local therapy==== | |
''Local therapy is planned to take place on week 9, as follows:'' | ''Local therapy is planned to take place on week 9, as follows:'' | ||
− | + | *[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible. | |
− | *Surgical removal of tumors is done when possible. | ||
*[[External beam radiotherapy]] to all metastatic sites of disease in addition to any radiation planned for primary tumor. | *[[External beam radiotherapy]] to all metastatic sites of disease in addition to any radiation planned for primary tumor. | ||
− | *If only radiation therapy is used, 4500 cGy | + | *If only radiation therapy is used, [[External beam radiotherapy]] 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy |
*Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease" | *Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease" | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. [ | + | # Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. [https://doi.org/10.1200/jco.2004.01.041 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15254055/ PubMed] |
− | |||
==VAdCA/IE {{#subobject:a6863c|Regimen=1}}== | ==VAdCA/IE {{#subobject:a6863c|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
VAdCA/IE: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | VAdCA/IE: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:a2770e|Variant=1}}=== | ===Regimen {{#subobject:a2770e|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2004.01.041 Miser et al. 2004] |
− | |style="background-color:#1a9851"|Phase | + | |1988-1992 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[#VAdCA|VAdCA]] | |[[#VAdCA|VAdCA]] | ||
− | |style="background-color:#ffffbf"| | + | |style="background-color:#ffffbf"|Did not meet co-primary endpoints of EFS/OS |
|- | |- | ||
|} | |} | ||
''Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.'' | ''Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.'' | ||
− | ====Chemotherapy, VAdCA portion==== | + | <div class="toccolours" style="background-color:#b3e2cd"> |
+ | ====Chemotherapy, VAdCA portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)==== | ||
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1 | *[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1 | ||
**Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 uses a capped dose and is from the same trial | **Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 uses a capped dose and is from the same trial | ||
Line 999: | Line 1,229: | ||
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses) | **Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses) | ||
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1 | ||
− | *[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative | + | *[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup> |
− | + | ====Chemotherapy, IE portion (cycles 2, 4, 6, 8, 10, 12, 14, 16)==== | |
− | + | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, with mesna | |
− | |||
− | ====Chemotherapy, IE portion==== | ||
− | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Supportive therapy, IE portion (cycles 2, 4, 6, 8, 10, 12, 14, 16)==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] with ifosfamide; primary reference did not list dosage/schedule |
− | *[[Mesna (Mesnex)]] with | + | '''21-day cycle for 17 cycles''' |
− | + | ====Local therapy==== | |
− | '''21-day cycle | ||
− | |||
''Local therapy is planned to take place on week 9, as follows:'' | ''Local therapy is planned to take place on week 9, as follows:'' | ||
− | + | *[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible. | |
− | *Surgical removal of tumors is done when possible. | ||
*[[External beam radiotherapy]] to all metastatic sites of disease in addition to any radiation planned for primary tumor. | *[[External beam radiotherapy]] to all metastatic sites of disease in addition to any radiation planned for primary tumor. | ||
− | *If only radiation therapy is used, 4500 cGy | + | *If only radiation therapy is used, [[External beam radiotherapy]] 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy |
*Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease" | *Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease" | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. [ | + | # Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. [https://doi.org/10.1200/jco.2004.01.041 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15254055/ PubMed] |
==VAI {{#subobject:547404|Regimen=1}}== | ==VAI {{#subobject:547404|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide | VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:020e4c|Variant=1}}=== | ===Regimen {{#subobject:020e4c|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003] |
− | |style="background-color:#91cf61"|Phase | + | |1998-01 to 1999-06 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ''This protocol was intended for patients with metastatic disease. The reference does not clearly describe how many cycles of VAI | + | ''Note: This protocol was intended for patients with metastatic disease. The reference does not clearly describe how many cycles of VAI were used.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#VIDE_2|VIDE]] for up to 6 cycles | + | *Induction [[#VIDE_2|VIDE]] for up to 6 cycles |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> IV once per day on days 1 & 2 | *[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2 | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous | ||
− | |||
'''21-day cycle for one or more cycles''' | '''21-day cycle for one or more cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#Busulfan_.26_Melphalan.2C_then_auto_HSCT|Busulfan & Melphalan, then auto HSCT]] | + | *[[#Busulfan_.26_Melphalan.2C_then_auto_HSCT|Busulfan & Melphalan, then auto HSCT]] consolidation |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for | + | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818/ PubMed] |
− | + | # '''R2Pulm:''' Dirksen U, Brennan B, Le Deley MC, Cozic N, van den Berg H, Bhadri V, Brichard B, Claude L, Craft A, Amler S, Gaspar N, Gelderblom H, Goldsby R, Gorlick R, Grier HE, Guinbretiere JM, Hauser P, Hjorth L, Janeway K, Juergens H, Judson I, Krailo M, Kruseova J, Kuehne T, Ladenstein R, Lervat C, Lessnick SL, Lewis I, Linassier C, Marec-Berard P, Marina N, Morland B, Pacquement H, Paulussen M, Randall RL, Ranft A, Le Teuff G, Wheatley K, Whelan J, Womer R, Oberlin O, Hawkins DS; Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators. High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol. 2019 Dec 1;37(34):3192-3202. Epub 2019 Sep 25. [https://doi.org/10.1200/JCO.19.00915 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881099/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31553693/ PubMed] [https://clinicaltrials.gov/study/NCT00987636 NCT00987636] | |
==VIDE {{#subobject:737059|Regimen=1}}== | ==VIDE {{#subobject:737059|Regimen=1}}== | ||
− | + | VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide< | ||
===Regimen {{#subobject:2601fd|Variant=1}}=== | ===Regimen {{#subobject:2601fd|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" |
− | !style="width: | + | !style="width: 25%"|Study |
− | !style="width: | + | !style="width: 25%"|Dates of enrollment |
− | !style="width: | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003] |
− | |style="background-color:#91cf61"|Phase | + | |1998-01 to 1999-06 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|ORR: 88% | |ORR: 88% | ||
|- | |- | ||
|} | |} | ||
− | ''This protocol was intended for patients with metastatic disease.'' | + | ''Note: This protocol was intended for patients with metastatic disease.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | *[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1 | ||
Line 1,078: | Line 1,304: | ||
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous | + | '''21-day cycle for up to 6 cycles''' |
− | + | </div> | |
− | '''21-day cycle for up to 6 | + | <div class="toccolours" style="background-color:#cbd5e7"> |
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[# | + | *[[#VAI_2|VAI]] consolidation, then [[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|HD with auto HSCT]] consolidation |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for | + | # Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818/ PubMed] |
− | + | [[Category:Ewing sarcoma regimens]] | |
− | [[Category:Ewing | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
− | |||
[[Category:Bone sarcomas]] | [[Category:Bone sarcomas]] |
Latest revision as of 17:44, 23 June 2024
Section editor | |
---|---|
Elizabeth J. Davis, MD Vanderbilt University Nashville, TN, USA |
Note: certain regimens have been moved to dedicated pages:
21 regimens on this page
34 variants on this page
|
Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
ESMO
- 2009: Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Paulussen et al. Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Saeter. Ewing's sarcoma of bone: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Saeter et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Ewing's sarcoma of bone PubMed
- 2003: Saeter. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Ewing's sarcoma of bone PubMed
NCCN
- NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Bone Cancer.
Neoadjuvant therapy
EVAIA
EVAIA: Etoposide, Vincristine, Adriamycin (Doxorubicin), Ifosfamide, DActinomycin
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paulussen et al. 2008 (EICESS-92) | 1992-1997 | Phase 3 (E-esc) | VAIA | Did not meet primary endpoint of EFS36 |
Note: This regimen is intended for high-risk patients.
Chemotherapy
- Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
- Vincristine (Oncovin) 1.5 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 2 & 4
- Ifosfamide (Ifex) 2000 mg/m2 IV once per day on days 1 to 3
- Note: primary reference does not comment about the use of mesna
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 4 cycles
Subsequent treatment
- Surgical removal of tumors is done when possible.
- EICESS-92, patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: Definitive external beam radiotherapy x 5440 cGy, then adjuvant EVAIA
- EICESS-92, patients with a good histologic response: Adjuvant External beam radiotherapy 4480 cGy, then adjuvant EVAIA
- Additional details about particular clinical scenarios can be found in the original reference
References
- EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains dosing details in manuscript PubMed NCT00002516
VACA
VACA: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Grier et al. 2003 (INT-0091) | 1988-1992 | Phase 3 (C) | VACA/IE | Inferior OS |
Note: The survival disadvantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.
Chemotherapy
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Doxorubicin (Adriamycin) 75 mg/m2 IV bolus once on day 1
- Stop once cumulative dose received by the patient exceeds 375 mg/m2
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
- Dactinomycin (Cosmegen) 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2
Supportive therapy
- Mesna (Mesnex) after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
21-day cycle for 17 cycles
Subsequent treatment
- Definitive local therapy is planned to take place on week 12
- Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
- INT-0091, residual tumor after surgery: 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
- If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Paulussen et al. 2001 (CESS 86) | 1986-01 to 1991-07 | Non-randomized |
Note: This regimen is intended for standard risk patients.
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1, 2, 43, 44
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1, then 400 mg/m2 IV once per day on days 22, 23, 24, then 1200 mg/m2 IV once on day 43
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 22, 23, 24
Supportive therapy
- Mesna (Mesnex) "as appropriate"
9-week "block", then proceed to local therapy:
Local therapy
- Complete surgical removal of tumors is done when possible.
- CESS 86, patients not undergoing surgery: External beam radiotherapy 6000 cGy to the tumor bulk, with the tumor-bearing compartment receiving at least 4480 cGy
- CESS 86, patients with incomplete surgical resection or poor histologic response: External beam radiotherapy 4480 cGy
Subsequent treatment
- Adjuvant VACA
References
- CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article contains dosing details in manuscript PubMed
- INT-0091: Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS; CCG; POG. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. link to original article contains dosing details in manuscript PubMed
VACA/IE
VACA/IE: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin alternating with Ifosfamide, Etoposide
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Grier et al. 2003 (INT-0091) | 1988-1992 | Phase 3 (E-esc) | VACA | Superior OS1 |
1The survival advantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis. The dosing schedule below assumes that the patient is doxorubicin-naive.
Induction
Chemotherapy, VACA portion (cycles 1 & 3)
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Doxorubicin (Adriamycin) 75 mg/m2 IV bolus once on day 1
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
Supportive therapy, VACA portion (cycles 1 & 3)
- Mesna (Mesnex) after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
Chemotherapy, IE portion (cycles 2 & 4)
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, with mesa
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, IE portion (cycles 2 & 4)
- Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule
21-day cycle for 4 cycles, followed by:
Definitive
Local therapy is planned to take place on week 12, as follows:
- Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
- INT-0091, residual tumor after surgery: 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
- If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
Consolidation
Chemotherapy, VACA portion
- Vincristine (Oncovin) as follows:
- Cycles 5, 7, 9, 11, 13: 2 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Doxorubicin (Adriamycin) as follows:
- Cycle 5: 75 mg/m2 IV bolus once on day 1
- Stop once cumulative dose received by the patient exceeds 375 mg/m2
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 5, 7, 9, 11, 13: 1200 mg/m2 IV once on day 1
- Dactinomycin (Cosmegen) as follows:
- Cycles 7, 9, 11, 13: 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2
Supportive therapy, VACA portion (cycles 5, 7, 9, 11, 13)
- Mesna (Mesnex) after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
Chemotherapy, IE portion (cycles 6, 8, 10, 12)
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, with mesna
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, IE portion (cycles 6, 8, 10, 12)
- Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule
21-day cycle for 13 cycles (17 total cycles of chemotherapy)
References
- INT-0091: Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. link to original article contains dosing details in manuscript PubMed
VAIA
VAIA: Vincristine, Adriamycin (Doxorubicin), Ifosfamide, Actinomycin-D (Dactinomycin)
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paulussen et al. 2008 (EICESS-92) | 1992-1997 | Phase 3 (C) | EVAIA (high-risk) | Did not meet primary endpoint of EFS36 |
Note: high-risk patients were randomized to this regimen versus EVAIA. Standard-risk patients were not randomized at this point of the protocol.
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 2 & 4
- Ifosfamide (Ifex) 2000 mg/m2 IV once per day on days 1 to 3
- Note: primary reference does not comment about the use of mesna
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 4 cycles, then proceed to local therapy:
Local therapy
- Surgical removal of tumors is done when possible.
- EICESS-92, patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: External beam radiotherapy 5440 cGy
- EICESS-92, patients with a good histologic response: External beam radiotherapy 4480 cGy
- Additional details about particular clinical scenarios can be found in the original reference
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Paulussen et al. 2001 (CESS 86) | 1986-01 to 1991-07 | Non-randomized |
Note: This regimen is intended for high risk patients.
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1, 2, 43, 44
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1, 2, 22, 23, 43, 44
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 22, 23, 24
Supportive therapy
- Mesna (Mesnex) "as appropriate"
9-week "block", then proceed to local therapy:
Local therapy
- Complete surgical removal of tumors is done when possible.
- CESS 86, patients not undergoing surgery: External beam radiotherapy 6000 cGy to the tumor bulk, with the tumor-bearing compartment receiving at least 4480 cGy
- CESS 86, patients with incomplete surgical resection or poor histologic response: External beam radiotherapy 4480 cGy
Subsequent treatment
- Adjuvant VAIA
References
- CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article contains dosing details in manuscript PubMed
- EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains dosing details in manuscript PubMed NCT00002516
- CWS/RMS-96: Sparber-Sauer M, Ferrari A, Kosztyla D, Ladenstein R, Cecchetto G, Kazanowska B, Scarzello G, Ljungman G, Milano GM, Niggli F, Alaggio R, Vokuhl C, Casanova M, Klingebiel T, Zin A, Koscielniak E, Bisogno G. Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer. 2022 Sep;69(9):e29691. Epub 2022 Apr 19. link to original article PubMed
VDC/IE
VDC/IE: Vincristine, Doxorubicin, Cyclophosphamide, alternating with Ifosfamide & Etoposide
VAdriaC/IE: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, alternating with Ifosfamide & Etoposide
Regimen variant #1, q2wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Womer et al. 2012 (COG AEWS0031) | 2001-05 to 2005-08 | Phase 3 (E-esc) | VDC/IE; standard | Seems to have superior EFS (primary endpoint) |
DuBois et al. 2023 (COG AEWS1221) | 2014-12 to 2019-03 | Phase 3 (C) | VDC/IE & Ganitumab | Did not meet primary endpoint of EFS |
Chemotherapy, VDC portion (cycles 1, 3, 5)
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Doxorubicin (Adriamycin) 37.5 mg/m2 IV once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
Supportive therapy, VDC portion (cycles 1, 3, 5)
- Mesna (Mesnex) with cyclophosphamide (dose/schedule not specified)
- Filgrastim (Neupogen) schedule not specified
Chemotherapy, IE portion (cycles 2, 4, 6)
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, with mesna
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, IE portion (cycles 2, 4, 6)
- Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule
- Filgrastim (Neupogen) schedule not specified
14-day cycle for 6 cycles (VDC/IE x 3)
Subsequent treatment
- Definitive local therapy, then adjuvant VDC/IE
Regimen variant #2, q2wk with extra vincristine
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Leavey et al. 2021 (COG AEWS1031) | 2010-11-22 to 2016-01-04 | Phase 3 (C) | VDC/IE/VTC | Did not meet primary endpoint of EFS |
Note: the only difference between this and the variant above is the additional dose of vincristine in the second week of each VDC cycle.
Chemotherapy, VDC portion (cycles 1, 3, 5)
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 37.5 mg/m2 IV once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
Chemotherapy, IE portion (cycles 2, 4, 6)
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, both portions (cycles 1 to 6)
- Filgrastim (Neupogen) details not specified
14-day cycle for 6 cycles (VDC/IE x 3)
Subsequent treatment
- Definitive local therapy, then VDC/IE continuation
Regimen variant #3, q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Womer et al. 2012 (COG AEWS0031) | 2001-05 to 2005-08 | Phase 3 (C) | VDC/IE; dose-intense | Seems to have inferior EFS |
Chemotherapy, VDC portion (cycles 1 & 3)
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Doxorubicin (Adriamycin) 37.5 mg/m2 IV once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
Supportive therapy, VDC portion (cycles 1 & 3)
- Mesna (Mesnex) with cyclophosphamide; primary reference did not list dosage/schedule
- Filgrastim (Neupogen)
Chemotherapy, IE portion (cycles 2 & 4)
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, with mesna
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, IE portion (cycles 2 & 4)
- Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule
- Filgrastim (Neupogen)
21-day cycle for 4 cycles
Subsequent treatment
- Definitive local therapy, then adjuvant VDC/IE
References
- COG AEWS0031: Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR; Children's Oncology Group. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012 Nov 20;30(33):4148-54. Epub 2012 Oct 22. Erratum in: J Clin Oncol. 2015 Mar 1;33(7):814. Dosage error in article text. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00006734
- Update: Cash T, Krailo MD, Buxton AB, Pawel BR, Healey JH, Binitie O, Marcus KJ, Grier HE, Grohar PJ, Reed DR, Weiss AR, Gorlick R, Janeway KA, DuBois SG, Womer RB. Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031. J Clin Oncol. 2023 Oct 20;41(30):4724-4728. Epub 2023 Aug 31. link to original article PubMed
- COG AEWS1031: Leavey PJ, Laack NN, Krailo MD, Buxton A, Randall RL, DuBois SG, Reed DR, Grier HE, Hawkins DS, Pawel B, Nadel H, Womer RB, Letson GD, Bernstein M, Brown K, Maciej A, Chuba P, Ahmed AA, Indelicato DJ, Wang D, Marina N, Gorlick R, Janeway KA, Mascarenhas L. Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report. J Clin Oncol. 2021 Dec 20;39(36):4029-4038. Epub 2021 Oct 15. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01231906
- COG AEWS1221: DuBois SG, Krailo MD, Glade-Bender J, Buxton A, Laack N, Randall RL, Chen HX, Seibel NL, Boron M, Terezakis S, Hill-Kayser C, Hayes A, Reid JM, Teot L, Rakheja D, Womer R, Arndt C, Lessnick SL, Crompton BD, Kolb EA, Daldrup-Link H, Eutsler E, Reed DR, Janeway KA, Gorlick RG. Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2023 Apr 10;41(11):2098-2107. Epub 2023 Jan 20. link to original article link to PMC article PubMed NCT02306161
VIDE
VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Juergens et al. 2006 (EURO-E.W.I.N.G. 99) | NR | Phase 2 |
Koch et al. 2022 (Ewing 2008R3) | 2009-2018 | Non-randomized part of phase 3 RCT |
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV push once on day 1
- Ifosfamide (Ifex) 3000 mg/m2 IV over 1 to 3 hours once per day on days 1 to 3
- Doxorubicin (Adriamycin) 20 mg/m2 IV over 4 hours once per day on days 1 to 3
- Etoposide (Vepesid) 150 mg/m2 IV over 60 minutes once per day on days 1 to 3
Supportive therapy
- Mesna (Mesnex) 1000 mg/m2 IV push once on day 1; 60 minutes prior to ifosfamide, then 3000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 10,000 mg/m2)
- 2 to 3 liters/m2 hydration per day
- Recommended, but not required: Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 13, starting 24 hours after completion of chemotherapy
21-day cycle for 6 cycles
Subsequent treatment
- EURO-E.W.I.N.G. 99: Further therapy is dictated by patient characteristics & response; details can be found in the primary reference
- Ewing 2008R3: Surgery when feasible followed by adjuvant VAC x 8 or VAI x 8, then Treosulfan & Melphalan, then auto HSCT consolidation versus No further treatment
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Strauss et al. 2003 | 1998-01 to 1999-06 | Phase 2 |
Chemotherapy
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 to 3
- Doxorubicin (Adriamycin) 20 mg/m2 IV once per day on days 1 to 3
- Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m2)
21-day cycle for up to 6 cycles
Subsequent treatment
- Strauss et al. 2003, patients with resectable localized disease: complete surgical removal of tumors when possible, then adjuvant VAI
- Strauss et al. 2003, patients with unresectable localized disease: VAI & RT consolidation
References
- Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article contains dosing details in manuscript PubMed
- EURO-E.W.I.N.G. 99: Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-EWING 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. link to original article contains dosing details in abstract PubMed
- Euro-EWING99-R1: Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. link to original article does not contain dosing details PubMed NCT00020566
- Ewing 2008R3: Koch R, Gelderblom H, Haveman L, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Eich HT, Renard M, Hauser P, Burdach S, Bovee J, Bonar F, Reichardt P, Kruseova J, Hardes J, Kühne T, Kessler T, Collaud S, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Hong A, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Metzler M, Hartmann W, Hjorth L, Bhadri V, Dirksen U. High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. J Clin Oncol. 2022 Jul 20;40(21):2307-2320. Epub 2022 Apr 15. link to original article contains dosing details in supplement PubMed NCT00987636
- EURO EWING 2012: Brennan B, Kirton L, Marec-Bérard P, Gaspar N, Laurence V, Martín-Broto J, Sastre A, Gelderblom H, Owens C, Fenwick N, Strauss S, Moroz V, Whelan J, Wheatley K. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet. 2022 Oct 29;400(10362):1513-1521. link to original article PubMed
- Ewing 2008R1: Koch R, Haveman L, Ladenstein R, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Kager L, Renard M, Hauser P, Burdach S, Bovee JVMG, Hong AM, Reichardt P, Kruseova J, Streitbürger A, Kühne T, Kessler T, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Bonar F, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Hartmann W, Hjorth L, Bhadri VA, Metzler M, Gelderblom H, Dirksen U. Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial. Clin Cancer Res. 2023 Dec 15;29(24):5057-5068. link to original article PubMed EudraCT 2008-003658-13
Adjuvant therapy
Busulfan & Melphalan, then auto HSCT
BuMel: Busulfan & Melphalan
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Atra et al. 1997 | NR | Phase 2, fewer than 20 pts | ||
Whelan et al. 2018 (R2Loc) | 2000-2015 | Phase 3 (E-esc) | VAI | Seems to have superior OS (secondary endpoint) |
Chemotherapy
- Busulfan (Myleran) 1 mg/kg PO every 6 hours on days -5 to -2 (total dose of 16 mg/kg)
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. link to original article contains dosing details in manuscript PubMed
- R2Loc: Whelan J, Le Deley MC, Dirksen U, Le Teuff G, Brennan B, Gaspar N, Hawkins DS, Amler S, Bauer S, Bielack S, Blay JY, Burdach S, Castex MP, Dilloo D, Eggert A, Gelderblom H, Gentet JC, Hartmann W, Hassenpflug WA, Hjorth L, Jimenez M, Klingebiel T, Kontny U, Kruseova J, Ladenstein R, Laurence V, Lervat C, Marec-Berard P, Marreaud S, Michon J, Morland B, Paulussen M, Ranft A, Reichardt P, van den Berg H, Wheatley K, Judson I, Lewis I, Craft A, Juergens H, Oberlin O; Euro-EWING-99 and EWING-2008 Investigators. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-EWING99 and Ewing-2008. J Clin Oncol. 2018 Nov 1;36(31):3110-9. Epub 2018 Sep 6. link to original article contains dosing details in supplement link to PMC article PubMed NCT00020566
EVAIA
EVAIA: Etoposide, Vincristine, Adriamycin (Doxorubicin), Ifosfamide, DActinomycin
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Paulussen et al. 2008 (EICESS-92) | 1992-1997 | Non-randomized part of phase 3 RCT |
Note: This regimen is intended for high-risk patients.
Preceding treatment
- Neoadjuvant EVAIA, then local therapy
Chemotherapy
- Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
- Vincristine (Oncovin) 1.5 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 2 & 4
- Ifosfamide (Ifex) 2000 mg/m2 IV once per day on days 1 to 3
- Note: primary reference does not comment about the use of Mesna (Mesnex)
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 10 cycles
References
- EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains dosing details in manuscript PubMed NCT00002516
VACA
VACA: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paulussen et al. 2008 (EICESS-92) | 1992-1997 | Phase 3 (E-switch-ic) | VAIA | Did not meet primary endpoint of EFS36 |
Note: this regimen was intended for standard-risk patients.
Preceding treatment
- Neoadjuvant VAIA, then local therapy
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 2 & 4
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 10 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Paulussen et al. 2001 (CESS 86) | 1986-01 to 1991-07 | Non-randomized |
Note: This regimen is intended for standard risk patients.
Preceding treatment
- Neoadjuvant VACA, then local therapy
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1, 2, 43, 44
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1, then 400 mg/m2 IV once per day on days 22, 23, 24, then 1200 mg/m2 IV once on day 43
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 22, 23, 24
Supportive therapy
- Mesna (Mesnex) "as appropriate"
9-week "block" for 3 blocks
Regimen variant #3
Study | Dates of enrollment | Evidence |
---|---|---|
Craft et al. 1997 (ET-1) | 1978-1986 | Non-randomized (RT) |
Preceding treatment
- Induction VAC, then Cyclophosphamide, Vincristine, RT with consideration for surgery
Chemotherapy
- Vincristine (Oncovin) 2 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) as follows:
- Cycles 1, 3, 5, 7: 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 (maximum dose of 1000 mg) IV once on day 1
- Dactinomycin (Cosmegen) as follows:
- Cycles 2, 4, 6, 8, 12, 14, 16, 18: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
21-day cycle for 18 cycles (1 year)
References
- ET-1: Craft AW, Cotterill SJ, Bullimore JA, Pearson D; United Kingdom Children's Cancer Study Group; Medical Research Council Bone Sarcoma Working Party. Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). Eur J Cancer. 1997 Jun;33(7):1061-9. link to original article contains dosing details in manuscript PubMed
- CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article contains dosing details in manuscript PubMed
- EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains dosing details in manuscript PubMed NCT00002516
VAI
VAI: Vincristine, DActinomycin, Ifosfamide
IVA: Ifosfamide, Vincristine, DActinomycin
Regimen variant #1, capped dactinomycin
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Le Deley et al. 2014 (Euro-EWING99-R1) | 2000-2010 | Phase 3 (C) | VAC | Inconclusive whether non-inferior EFS |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
- Neoadjuvant VIDE x 6, then complete surgical excision if feasible; radiotherapy if surgery incomplete or infeasible
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Dactinomycin (Cosmegen) 0.75 mg/m2 (maximum dose of 1.5 mg) IV once per day on days 1 & 2
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 & 2
Supportive therapy
- Mesna (Mesnex) is not described
21-day cycle for 8 cycles
Regimen variant #2, uncapped dactinomycin
Study | Dates of enrollment | Evidence |
---|---|---|
Strauss et al. 2003 | 1998-01 to 1999-06 | Phase 2 |
Preceding treatment
- Neoadjuvant VIDE, then local therapy if it was possible
Chemotherapy
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Dactinomycin (Cosmegen) 0.75 mg/m2 IV once per day on days 1 & 2
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 & 2
- If appropriate, concurrent radiation therapy given sometime during the first 3 cycles
Supportive therapy
- Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m2)
21-day cycle for up to 8 cycles
References
- Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article contains dosing details in manuscript PubMed
- Euro-EWING99-R1: Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. link to original article contains dosing details in manuscript PubMed NCT00020566
VAIA
VAIA: Vincristine, Adriamycin (Doxorubicin), Ifosfamide, Actinomycin-D (Dactinomycin)
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paulussen et al. 2008 (EICESS-92) | 1992-1997 | Phase 3 (C) | VACA (standard-risk) | Did not meet primary endpoint of EFS36 |
Note: standard-risk patients were randomized to this regimen versus VACA. High-risk patients were not randomized at this point of the protocol.
Preceding treatment
- Neoadjuvant VAIA, then local therapy
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 2 & 4
- Ifosfamide (Ifex) 2000 mg/m2 IV once per day on days 1 to 3
- Note: primary reference does not comment about the use of mesna
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 1, 3, 5
21-day cycle for 10 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Paulussen et al. 2001 (CESS 86) | 1986-01 to 1991-07 | Non-randomized |
Note: This regimen was intended for high risk patients.
Preceding treatment
- Neoadjuvant VAIA, then local therapy
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1, 2, 43, 44
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1, 2, 22, 23, 43, 44
- Dactinomycin (Cosmegen) 0.5 mg/m2 IV once per day on days 22, 23, 24
Supportive therapy
- Mesna (Mesnex) "as appropriate"
9-week "block" for 3 blocks
References
- CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article contains dosing details in manuscript PubMed
- EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains dosing details in manuscript PubMed NCT00002516
Relapsed or refractory or metastatic
Busulfan & Melphalan, then auto HSCT
Regimen variant #1, PO busulfan, mel 140 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Atra et al. 1997 | NR | Phase 2, fewer than 20 pts |
Chemotherapy
- Busulfan (Myleran) 1 mg/kg PO every 6 hours on days -5 to -2 (total dose of 16 mg/kg)
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
Regimen variant #2, PO busulfan, mel 160 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Atra et al. 1997 | NR | Phase 2, fewer than 20 pts |
Chemotherapy
- Busulfan (Myleran) 1 mg/kg PO every 6 hours on days -5 to -2 (total dose of 16 mg/kg)
- Melphalan (Alkeran) 160 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
Regimen variant #3, IV busulfan
Study | Dates of enrollment | Evidence |
---|---|---|
Strauss et al. 2003 | 1998-01 to 1999-06 | Phase 2 |
Note that melphalan is reported as given on day 2 (not day -2) in the original reference but this is surely an error.
Preceding treatment
- Adjuvant VAI x 1 or more cycles
Chemotherapy
- Busulfan (Myleran) 150 mg/m2 IV once per day on days -6 to -3
- Melphalan (Alkeran) 140 mg/m2 IV once on day -2
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. link to original article contains dosing details in manuscript PubMed
- Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article contains dosing details in manuscript PubMed
Cyclophosphamide & Topotecan
Regimen variant #1, standard-dose
Study | Dates of enrollment | Evidence |
---|---|---|
Saylors et al. 2001 | NR | Phase 2 |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.
Chemotherapy
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
- Topotecan (Hycamtin) 0.75 mg/m2 IV over 30 minutes once per day on days 1 to 5, given second
Supportive therapy
- 500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
- Antiemetics once per day on days 1 to 5, prior to chemotherapy
- 3 liters/m2 IV or PO over 24 hours after chemotherapy
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 1500/μL above nadir
21-day cycle for 12 to 14 cycles
Regimen variant #2, standard-dose with local therapy
Study | Dates of enrollment | Evidence |
---|---|---|
Hunold et al. 2006 | 1998-09 to 2004-04 | Phase 2 |
Note: Some guidelines state that vincristine can be added to this regimen. No primary reference for this is available.
Chemotherapy
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 minutes once per day on days 1 to 5
- Topotecan (Hycamtin) 0.75 mg/m2 IV over 30 minutes once per day on days 1 to 5
Supportive therapy
- Mesna (Mesnex), antiemetics, fluids, and Filgrastim (Neupogen) "according to institutional standards"
21-day cycle for 12 to 14 cycles
Subsequent treatment
- Hunold et al. 2006, surgical candidate lesions: Surgical removal of tumors is done when possible.
- Hunold et al. 2006, all other lesions: Definitive External beam radiotherapy
Regimen variant #3, high-dose
Study | Dates of enrollment | Evidence |
---|---|---|
Kushner et al. 2000 | NR | Non-randomized |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.
Chemotherapy
- Cyclophosphamide (Cytoxan) 2100 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given second (total dose per cycle: 4200 mg/m2)
- Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 140 mg/kg)
- Topotecan (Hycamtin) 2 mg/m2/day IV continuous infusion over 72 hours, started on day 1, given third (total dose per cycle: 6 mg/m2)
Supportive therapy
- Mesna (Mesnex) 2100 mg/m2/day IV continuous infusion over 72 hours, started on day 1, given first (total dose per cycle: 6300 mg/m2)
- Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 210 mg/kg)
- If body surface area less than 1 m2, mesna is given in 500 mL NS over 24 hours
- If body surface area is at least 1 m2, mesna is given in 1000 mL NS over 24 hours
- Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 210 mg/kg)
- On day 1, prior to chemotherapy, 20 mL/kg NS IV over 30 minutes, then D5 1/2 NS with 15 mEq KCl per 500 mL at 200 mL/m2/H until urine specific gravity less than 1.010, then start mesna & cyclophosphamide
- Additional hydration fluid on days 1 & 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3000 mL/m2/24 hours
- Additional hydration fluid on day 3 at 150 mL/m2/hour for 6 to 12 hours after completion of cyclophosphamide infusion
- Cyclophosphamide is given in D5NS with 10 mEq potassium chloride (KCl) and 5 mg Furosemide (Lasix) per 500 mL fluid. 500 mL total volume is used for patients with body surface area less than 1 m2; 1000 mL total volume is used for patients with BSA of at least 1 m2
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 5, to continue until ANC is at least 1000/μL
Subsequent cycles to start when ANC greater than 1000/μL and platelets greater than 75 x 109/L
References
- Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000 Nov;35(5):468-74. link to original article contains dosing details in manuscript PubMed
- Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. link to original article contains dosing details in manuscript PubMed
- Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006 Nov;47(6):795-800. link to original article contains dosing details in manuscript PubMed
Docetaxel & Gemcitabine
Regimen
Study | Evidence |
---|---|
Navid et al. 2008 | Retrospective |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available. Only 2 of the 22 patients in this retrospective review had Ewing sarcoma.
Chemotherapy
- Docetaxel (Taxotere) 75 to 100 mg/m2 IV over 60 minutes once on day 8, given second
- Gemcitabine (Gemzar) 675 mg/m2 IV over 90 minutes once per day on days 1 & 8, given first on day 8
Supportive therapy
- Ondansetron (Zofran) once per day on days 1 & 8, prior to chemotherapy
- Dexamethasone (Decadron) starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel
- H1 or H2 blockers such as Diphenhydramine (Benadryl) and Ranitidine (Zantac) prior to chemotherapy on days 1 & 8 per physician discretion
- Some patients received Filgrastim (Neupogen) starting on day 9
21-day cycles
References
- Retrospective: Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. link to original article contains dosing details in manuscript PubMed
ICE
ICE: Ifosfamide, Carboplatin, Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Van Winkle et al. 2005 (CCG-0894) | 1992-06 to 1994-11 | Phase 2 |
Van Winkle et al. 2005 (CCG-0924) | 1993-07 to 1995-04 | Phase 1, >20 pts |
Van Winkle et al. 2005 (CCG-0931) | 1994-05 to 1996-12 | Non-randomized, <20 pts |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available. The reference did not mention Mesna (Mesnex) being used.
Chemotherapy
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5
- Carboplatin (Paraplatin) 400 mg/m2 IV "for 2 days"
- Note: the reference did not explicitly say which 2 days carboplatin should be given on
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy
- Depending on the study the patients were enrolled on, they received one of the following:
- CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/μL, or until ANC is at least 1000/μL above nadir, whichever comes later
- CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m2 SC once per day or 500 mcg/m2 SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/μL or platelet count is at least 900 x 109/L for 2 days between days 13 to 18, or until ANC is at least 1000/μL and platelet count is at least 100 x 109/L, whichever comes later
- CCG-0931: Filgrastim (Neupogen) 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/μL, and IL-6 is continued until platelets are at least 100 x 109/L for 2 consecutive days or until day 35, whichever comes sooner.
21-day cycles, with next cycle starting as soon as ANC is at least 1000/μL and platelet count is at least 100 x 109/L
Subsequent treatment
- Resection of disease was allowed after 4 cycles based on patient's response to ICE
References
- Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains dosing details in manuscript PubMed
IE
IE: Ifosfamide, Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Miser et al. 1987 | 1985-06 to 1986-06 | Phase 2 |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.
Chemotherapy
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, given second, with loading dose of mesna
- Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes once per day on days 1 to 5, given first
Supportive therapy
- Mesna (Mesnex) 360 mg/m2 IV loading dose over 1 hour, given with ifosfamide, then 120 mg/m2/hour IV over 3 hours, then 360 mg/m2 IV or PO over 15 minutes every 3 hours for 6 doses, given at hours 5, 8, 11, 14, 17, 20
21-day cycle for 12 cycles
Subsequent treatment
- Miser et al. 1987, patients responding to therapy after 4 cycles: local therapy with surgery or radiation is used to try to achieve a complete remission.
- Radiation therapy consisted of 180 cGy fractions given for a total dose of 50 to 5500 cGy.
References
- Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, Wesley R, Magrath I. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987 Aug;5(8):1191-8. link to original article contains dosing details in manuscript PubMed
Irinotecan & Temozolomide
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Wagner et al. 2004 | 2002-01 to 2003-02 | Phase 1, fewer than 20 pts |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available. Note that irinotecan 15 mg/m2 was also studied, but this dose was not recommended due to dose-limiting toxicities of diarrhea and infection.
Chemotherapy
- Irinotecan (Camptosar) 10 mg/m2 IV over 60 minutes once per day on days 1 to 5, 8 to 12, given second on days 1 to 5, 1 hour after temozolomide
- Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5, given first
Supportive therapy
- Loperamide (Imodium) prn diarrhea
28-day cycles
Regimen variant #2
Study | Evidence |
---|---|
Casey et al. 2009 | Retrospective |
Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.
Chemotherapy
- Irinotecan (Camptosar) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5, 8 to 12, given second on days 1 to 5, 1 hour after temozolomide
- Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5, given first
Supportive therapy
- Cefixime (Suprax) prophylaxis starting 1 to 2 days prior to irinotecan, continuing until the completion of each cycle
- Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg PO three times per day during irinotecan therapy
- Loperamide (Imodium) prn diarrhea
- Patient "advised to maintain hydration"
21-day cycles
References
- Phase I: Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004 Feb 1;10(3):840-8. link to original article contains dosing details in manuscript PubMed
- Retrospective: Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007 Feb;48(2):132-9. link to original article PubMed
- Retrospective: Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, Meyers PA. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009 Dec;53(6):1029-34. link to original article contains dosing details in manuscript PubMed
TC, then IE, VDoxoC, VEC
TC, then IE, VDoxoC, VEC: Topotecan, Cyclophosphamide followed by Ifosfamide, Etoposide, then Vincristine, Doxorubicin, Cyclophosphamide, then Vincristine, Etoposide, Cyclophosphamide
Study | Dates of enrollment | Evidence |
---|---|---|
Bernstein et al. 2006 (POG 9457) | NR | Phase 2 |
Note: This was a complex regimen, and it is suggested to refer to the primary reference and figure 1 for the protocol schema. One arm of patients in this trial received Amifostine (Ethyol), but its usage is not described below since it did not result in improved outcomes. Treatment starts with an optional topotecan window for stable patients without significantly impaired function or life-threatening disease:
Topotecan window
Chemotherapy
- Topotecan (Hycamtin) 2.4 mg/m2 IV once per day on days 1 to 5
Supportive therapy
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/μL above nadir
5-day course, followed by upfront window, starting at week 0:
Upfront window
Chemotherapy
- Topotecan (Hycamtin) 0.75 mg/m2 IV over 30 minutes once per day on days 1 to 5
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
Supportive therapy
- Prehydration with 500 mL/m2 D5 1/4 NS
- 1500 mL/m2 IV or PO hydration continuous for 24 hours after chemotherapy
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/μL above nadir
21-day cycle for up to 2 cycles Patients with progression after the first cycle moved immediately to induction therapy; others proceeded to induction after the second cycle, starting at week 6 with IE:
Induction
Chemotherapy, IE portion
- Ifosfamide (Ifex) as follows:
- Cycle 1: 3600 mg/m2 IV over 2 hours once per day on days 1 to 5, given second, after etoposide
- Administered in 200 mL/m2 D5 1/2 NS
- Cycles 2 & 3: 2800 mg/m2 IV over 2 hours once per day on days 1 to 5, given second, after etoposide
- Administered in 200 mL/m2 D5 1/2 NS
- Cycle 1: 3600 mg/m2 IV over 2 hours once per day on days 1 to 5, given second, after etoposide
- Etoposide (Vepesid) 100 mg/m2 IV over 45 minutes once per day on days 1 to 5, given first, before ifosfamide
- Administered in 250 mL/m2 of D5 1/2 NS
Supportive therapy, IE portion
- Mesna (Mesnex) 4000 mg/m2 IV once per day on days 1 to 5
- "Vigorous hydration"
- Antiemetics
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day cycle for a total of 3 cycles, alternating with VDoxoC
Chemotherapy, VDoxoC portion
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV bolus once per day on days 1, 8, 15, given first
- Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given third (total dose per cycle: 75 mg/m2)
- Administered in 2400 mL/m2/day (4800 mL/m2 total volume) of D5 1/2 NS
- Cyclophosphamide (Cytoxan) 2100 mg/m2 IV over 30 minutes once per day on days 1 & 2, given second
- Administered in 200 mL/m2 D5 1/2 NS
Supportive therapy, VDoxoC portion
- Mesna (Mesnex) 2400 mg/m2 total dose IV; exact schedule not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 4, 24 hours after chemotherapy is complete
21-day cycle for a total of 2 cycles, alternating with IE Local therapy for primary disease along with ongoing chemotherapy starts at week 21:
Definitive therapy, primary
Chemotherapy, VDoxoC portion
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m2)
- Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1
Supportive therapy, VDoxoC portion
- Mesna (Mesnex), dosage & schedule not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day course, followed by local control:
Local therapy, after week 21
- Choice of modality between surgical and radiation therapy options is at the discretion of the provider
- POG 9457, patients treated with radiation alone: External beam radiotherapy 4500 cGy in 180 cGy fractions to the initial tumor volume; additional treatment up to a total of 5580 cGy was administered to original bony tumors and the postinduction chemotherapy soft tissue volumes plus a 2 cm margin
- See primary reference for details about radiation therapy in a variety of clinical scenarios
Chemotherapy, VEC portion
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1
Supportive therapy, VEC portion
- Use of Mesna (Mesnex) not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day cycle for 2 cycles, followed by:
Continuation
Chemotherapy, IE portion
- Ifosfamide (Ifex) 2100 mg/m2 IV once per day on days 1 to 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, IE portion
- Mesna (Mesnex), dosage & schedule not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day cycle for a total of 2 cycles, alternating with VDoxoC
Chemotherapy, VDoxoC portion
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
- Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m2)
- Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1
Supportive therapy, VDoxoC portion
- Mesna (Mesnex) dosage & schedule not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day course, in between IE Local therapy for metastatic disease along with ongoing chemotherapy starts at week 39:
Definitive therapy, metastases
Chemotherapy, VDoxoC potion
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Note: the day 8 dose is not described in the text but is described in figure 1
- Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m2)
- Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1
Supportive therapy, VDoxoC portion
- Mesna (Mesnex) dosage & schedule not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day course, followed by local control of metastatic disease:
Local therapy, metastatic disease (after week 39)
- Choice of modality between surgical and radiation therapy options is at the discretion of the provider
- External beam radiotherapy could be used to treat up to three sites of metastatic disease
- See primary reference for details about radiation therapy in a variety of clinical scenarios
Chemotherapy, VEC portion
- Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1
Supportive therapy, VEC portion
- Use of Mesna (Mesnex) not specified by reference
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
21-day cycle for 2 cycles
References
- POG 9457: Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group; Children's Oncology Group. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006 Jan 1;24(1):152-9. link to original article contains dosing details in manuscript PubMed NCT00002643
VAdCA
VAdCA: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miser et al. 2004 | 1988-1992 | Phase 3 (C) | VAdCA/IE | Did not meet co-primary endpoints of EFS/OS |
Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.
Chemotherapy
- Vincristine (Oncovin) 2 mg/m2 IV once on day 1
- Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 uses a capped dose and is from the same trial
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
- Stop once cumulative dose received by the patient exceeds 375 mg/m2 (after 5 courses)
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
- Dactinomycin (Cosmegen) 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2
21-day cycle for 17 cycles
Local therapy
Local therapy is planned to take place on week 9, as follows:
- Surgical removal of tumors is done when possible.
- External beam radiotherapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
- If only radiation therapy is used, External beam radiotherapy 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
- Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"
References
- Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article contains dosing details in manuscript PubMed
VAdCA/IE
VAdCA/IE: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin alternating with Ifosfamide, Etoposide
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miser et al. 2004 | 1988-1992 | Phase 3 (E-esc) | VAdCA | Did not meet co-primary endpoints of EFS/OS |
Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.
Chemotherapy, VAdCA portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)
- Vincristine (Oncovin) 2 mg/m2 IV once on day 1
- Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 uses a capped dose and is from the same trial
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
- Stop once cumulative dose received by the patient exceeds 375 mg/m2 (after 5 courses)
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
- Dactinomycin (Cosmegen) 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2
Chemotherapy, IE portion (cycles 2, 4, 6, 8, 10, 12, 14, 16)
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, with mesna
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy, IE portion (cycles 2, 4, 6, 8, 10, 12, 14, 16)
- Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule
21-day cycle for 17 cycles
Local therapy
Local therapy is planned to take place on week 9, as follows:
- Surgical removal of tumors is done when possible.
- External beam radiotherapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
- If only radiation therapy is used, External beam radiotherapy 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
- Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"
References
- Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article contains dosing details in manuscript PubMed
VAI
VAI: Vincristine, DActinomycin, Ifosfamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Strauss et al. 2003 | 1998-01 to 1999-06 | Phase 2 |
Note: This protocol was intended for patients with metastatic disease. The reference does not clearly describe how many cycles of VAI were used.
Preceding treatment
- Induction VIDE for up to 6 cycles
Chemotherapy
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Dactinomycin (Cosmegen) 0.75 mg/m2 IV once per day on days 1 & 2
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 & 2
Supportive therapy
- Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m2)
21-day cycle for one or more cycles
Subsequent treatment
- Busulfan & Melphalan, then auto HSCT consolidation
References
- Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article contains dosing details in manuscript PubMed
- R2Pulm: Dirksen U, Brennan B, Le Deley MC, Cozic N, van den Berg H, Bhadri V, Brichard B, Claude L, Craft A, Amler S, Gaspar N, Gelderblom H, Goldsby R, Gorlick R, Grier HE, Guinbretiere JM, Hauser P, Hjorth L, Janeway K, Juergens H, Judson I, Krailo M, Kruseova J, Kuehne T, Ladenstein R, Lervat C, Lessnick SL, Lewis I, Linassier C, Marec-Berard P, Marina N, Morland B, Pacquement H, Paulussen M, Randall RL, Ranft A, Le Teuff G, Wheatley K, Whelan J, Womer R, Oberlin O, Hawkins DS; Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators. High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol. 2019 Dec 1;37(34):3192-3202. Epub 2019 Sep 25. link to original article link to PMC article PubMed NCT00987636
VIDE
VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Strauss et al. 2003 | 1998-01 to 1999-06 | Phase 2 | ORR: 88% |
Note: This protocol was intended for patients with metastatic disease.
Chemotherapy
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 to 3
- Doxorubicin (Adriamycin) 20 mg/m2 IV once per day on days 1 to 3
- Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m2)
21-day cycle for up to 6 cycles
Subsequent treatment
- VAI consolidation, then HD with auto HSCT consolidation
References
- Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article contains dosing details in manuscript PubMed